thiourea and Pulmonary-Edema

Noninvasive, double-radioisotope measurement of pulmonary vascular protein leak is a specific and sensitive method for assessing pulmonary vascular permeability. It is sensitive enough to detect increases in vascular protein leak that are too small to produce detectable increases in gravimetric lung water. A simple method for calculating protein leak index reliably reflects expected changes in pulmonary vascular permeability in a broad range of lung injury conditions. This method of measurement may have significant experimental and clinical applications in the study of lung-injury-induced edema, and especially in the evaluation of levels of injury associated with increased permeability but not significant edema. In particular, this method may help to distinguish between increased-permeability edema, such as that which occurs in the adult respiratory distress syndrome, and other types of pulmonary edema in humans.

Topics: Animals; Blood Proteins; Capillary Permeability; Erythrocyte Count; Humans; Lung; Pulmonary Edema; Radioisotopes; Sheep; Thiourea; Time Factors

This article is a review of the current literature concerning the possible involvement of oxygen radicals in the development of pulmonary edema. The article focuses on changes in capillary endothelium caused by many different imposed experimental conditions that may be related to the generation of O2, OH. or H2O2. Data from our laboratory show that scavengers such as superoxide dismutase, dimethylsulfoxide, and catalase as well as leukocyte depletion provide partial protection to the very caustic alpha-naphthylthiourea. The literature concerning the possible involvement of leukocyte or tissue generation of oxygen radicals in the various forms of pulmonary edema is combined into a simple model that may explain why pathologic tissues show variable responses to compounds that should either scavenge the oxygen radicals or prevent leukocyte involvement.

Topics: Capillary Permeability; Catalase; Dimethyl Sulfoxide; Free Radicals; Humans; Leukocyte Count; Models, Biological; Oxygen; Pulmonary Edema; Superoxide Dismutase; Thiourea

We aimed to observe the possible effects of melatonin (MLT) deprivation (pinealectomy) and exogenous MLT administration on pulmonary edema induced by alpha-naphthylthiourea (ANTU), a toxic chemical agent, in rats. Seventy animals were assigned to seven groups: control, sham pinealectomy (PINX), PINX, ANTU (10 mg/kg intraperitoneal on day 30), ANTU + MLT (10 mg/kg/day i.p. for 30 days), ANTU + PINX, and ANTU + PINX + MLT.In this study, pleural effusion (PE) formation, lung weight/body weight (LW/BW) and PE/BW ratios (fluid accumulation and weight values in the lungs) increase detected. Pre-ANTU MLT administration led to significant decreases in PE, LW/BW, and PE/BW levels. The inhibited glutathione (GSH) and superoxide dismutase (SOD) levels and high malondialdehyde (MDA) levels that ANTU increase lipid peroxidation in the study. MLT administration eliminated oxidative stress by reducing MDA and ameliorating GSH and SOD levels.Pre-ANTU MLT administration led to a significant decrease in interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) levels in the lung when compared to the ANTU group without MLT administration. Post-pinealectomy ANTU administration significantly increased IL-1β and TNF-α levels when compared to ANTU and MLT administration without pinealectomy. Diffused inflammatory cell infiltration, interstitial pulmonary edema, and histopathological congestion were observed after the administration of ANTU. Severity of the damage was elevated in the ANTU + PINX group. MLT treatment regressed pulmonary effusion and edema and improves lung structure. In brief, the findings suggested that MLT inhibited proinflammatory mediators and could serve as a therapeutic agent to prevent inflammatory disorders.

Topics: Animals; Melatonin; Pinealectomy; Pulmonary Edema; Rats; Thiourea; Tumor Necrosis Factor-alpha

Alpha-naphthylthiourea (ANTU), a rodenticide induces lung toxicity. Chrysin a flavonoid possesses antioxidant, anti-inflammatory, and antihypertensive potential. The aim of this study was to evaluate the efficacy of chrysin against ANTU-induced pulmonary edema (PE) and pulmonary arterial hypertension (PAH) in laboratory rats. Sprague-Dawley rats were used to induce PE (ANTU, 10 mg/kg, ip) and PAH (ANTU, 5 mg/kg, ip, 4 weeks). Animals were treated with chrysin (10, 20, and 40 mg/kg) and various biochemical, molecular, and histological parameters were evaluated. Acute administration of ANTU induces PE revealed by significant (P < 0.05) increase in relative lung weight, pleural effusion volume, lung edema, bronchoalveolar lavage fluid cell counts, total protein, 5-hydroxytryptamine (5-HT), lactate dehydrogenase (LDH), and γ-glutamyl transferase (GGT), whereas pretreatment with chrysin (20 and 40 mg/kg, ip) significantly (P < 0.05) attenuated these ANTU-induced biochemical and histological alterations. Repeated administration of ANTU caused induction of PAH evaluated by significant (P < 0.05) alterations in electrocardiographic, hemodynamic changes, and left ventricular function, whereas chrysin (20 and 40 mg/kg, p.o.) treatment significantly (P < 0.05) attenuated these alterations. ANTU-induced hematological and serum biochemical (aspartate transaminase, alanine transaminase, LDH, and creatinine kinase MB) alterations were significantly (P < 0.05) inhibited by chrysin. It also significantly (P < 0.05) decreased elevated levels of oxido-nitrosative stress in the right ventricle (RV) and lung. Chrysin significantly (P < 0.05) attenuated downregulated endothelial nitric oxide synthase and upregulated vascular endothelial growth factor messenger RNA and protein expressions both in the RV and pulmonary artery. Chrysin inhibited ANTU-induced PE and PAH via modulation of inflammatory responses (5-HT, LDH, and GGT), oxido-nitrosative stress, and VEGF and eNOs levels.

Topics: Animals; Flavonoids; Hypertension, Pulmonary; Lung; Male; Nitric Oxide Synthase Type III; Pulmonary Artery; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Thiourea; Vascular Endothelial Growth Factor A

The capacity of the lung to clear edema fluid has been shown to be one of the factors that can influence the prognosis of cardiogenic and noncardiogenic pulmonary edema. Active Na+ transport across the alveolar epithelium is the main driving force involved in this physiological process. Since endogenous catecholamines are known to activate the sodium-dependent mechanism of alveolar edema clearance, the objective of the present study was to explore if adrenalectomy, which prevents the release of endogenous catecholamines and other hormones, such as corticosterone, into circulation, would affect edema resolution in a model of lung injury induced by thiourea.. A high-permeability pulmonary edema was induced in adult male Sprague-Dawley rats using a thiourea-induced pulmonary edema model. To determine if the release of adrenalin and corticosterone is essential for resolution of the thiourea-induced edema, we measured 1) the release of adrenalin and corticosterone in urine and 2) edema resolution in control animals and adrenalectomized animals.. The administration of thiourea significantly increased the wet-to-dry ratio after four and eight hours. After 12 and 24 hours, the wet-to-dry ratio gradually returned to baseline. Although thiourea-induced pulmonary edema was associated with a significant increase in urine adrenalin and corticosterone, the absence of adrenalin and corticosterone response in adrenalectomized animals did not prevent the resolution of the edema.. These experiments demonstrated that resolution of thioureainduced pulmonary edema can occur in the absence of hormonal secretion by the adrenal glands.

Topics: Adrenalectomy; Animals; Lung; Male; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Thiourea

We assessed the effects of dexmedetomidine in a rat model of α-naphthylthiourea (ANTU)-induced acute lung injury.. Forty Wistar Albino male rats weighing 200-240 g were divided into 5 groups (n = 8 each), including a control group. Thus, there were one ANTU group and three dexmedetomidine groups (10-, 50-, and 100-μg/kg treatment groups), plus a control group. The control group provided the normal base values. The rats in the ANTU group were given 10 mg/kg of ANTU intraperitoneally and the three treatment groups received 10, 50, or 100 μg/kg of dexmedetomidine intraperitoneally 30 min before ANTU application. The rat body weight (BW), pleural effusion (PE), and lung weight (LW) of each group were measured 4 h after ANTU administration. The histopathologic changes were evaluated using hematoxylin-eosin staining.. The mean PE, LW, LW/BW, and PE/BW measurements in the ANTU group were significantly greater than in the control groups and all dexmedetomidine treatment groups (P < 0.05). There were also significant decreases in the mean PE, LW, LW/BW and PE/BW values in the dexmedetomidine 50-μg/kg group compared with those in the ANTU group (P < 0.01). The inflammation, hemorrhage, and edema scores in the ANTU group were significantly greater than those in the control or dexmedetomidine 50-μg/kg group (P < 0.01).. Dexmedetomidine treatment has demonstrated a potential benefit by preventing ANTU-induced acute lung injury in an experimental rat model. Dexmedetomidine could have a potential protective effect on acute lung injury in intensive care patients.

Topics: Acute Lung Injury; Adrenergic alpha-2 Receptor Agonists; Animals; Dexmedetomidine; Disease Models, Animal; Drug Interactions; Lung; Male; Pleural Effusion; Pneumonia; Pulmonary Edema; Rats; Rats, Wistar; Rodenticides; Thiourea

We have previously demonstrated that adenosine plus homocysteine enhanced endothelial basal barrier function and protected against agonist-induced barrier dysfunction in vitro through attenuation of RhoA activation by inhibition of isoprenylcysteine-O-carboxyl methyltransferase. In the current study, we tested the effect of elevated adenosine on pulmonary endothelial barrier function in vitro and in vivo. We noted that adenosine alone dose dependently enhanced endothelial barrier function. While adenosine receptor A(1) or A(3) antagonists were ineffective, an adenosine transporter inhibitor, NBTI, or a combination of DPMX and MRS1754, antagonists for adenosine receptors A(2A) and A(2B), respectively, partially attenuated the barrier-enhancing effect of adenosine. Similarly, inhibition of both A(2A) and A(2B) receptors with siRNA also blunted the effect of adenosine on barrier function. Interestingly, inhibition of both transporters and A(2A)/A(2B) receptors completely abolished adenosine-induced endothelial barrier enhancement. The adenosine receptor A(2A) and A(2B) agonist, NECA, also significantly enhanced endothelial barrier function. These data suggest that both adenosine transporters and A(2A) and A(2B) receptors are necessary for exerting maximal effect of adenosine on barrier enhancement. We also found that adenosine enhanced Rac1 GTPase activity and overexpression of dominant negative Rac1 attenuated adenosine-induced increases in focal adhesion complexes. We further demonstrated that elevation of cellular adenosine by inhibition of adenosine deaminase with Pentostatin significantly enhanced endothelial basal barrier function, an effect that was also associated with enhanced Rac1 GTPase activity and with increased focal adhesion complexes and adherens junctions. Finally, using a non-inflammatory acute lung injury (ALI) model induced by alpha-naphthylthiourea, we found that administration of Pentostatin, which elevated lung adenosine level by 10-fold, not only attenuated the development of edema before ALI but also partially reversed edema after ALI. The data suggest that adenosine deaminase inhibition may be useful in treatment of pulmonary edema in settings of ALI.

Topics: Acute Lung Injury; Adenosine; Adenosine Deaminase Inhibitors; Adherens Junctions; Animals; Cattle; Endothelium; Endothelium, Vascular; Focal Adhesions; Lung; Male; Nucleoside Transport Proteins; Pentostatin; Pulmonary Edema; rac1 GTP-Binding Protein; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A; Receptor, Adenosine A2B; Receptors, Adenosine A2; Thiourea

Antiedematous activity of new thiazolo[5,4-b]indole derivatives containing a fragment of isothiourea and characterized by higher antihypoxic activity compared to known antihypoxants was studied on a model of toxic edema of the lungs in mice. Compounds exhibiting high activity on two models of hypoxia (hypobaric and hemic) better protected from lung edema than compounds active only in hypobaric hypoxia.

Topics: Animals; Hypoxia; Indoles; Kinetics; Lung; Male; Mice; Models, Chemical; Phosgene; Pulmonary Edema; Rats; Thiazoles; Thiourea

This study was designed to investigate the possible participation of morphine in pulmonary oedema induced by alpha-naphthylthiourea (ANTU), which is a well-known noxious chemical agent in the lung. Injection of ANTU (15 mg/kg i.p.) produced pulmonary oedema as indicated by an increase in lung weight/body weight ratio and pleural effusion reaching a maximum within 4 h in rat. Administration of morphine prior to ANTU significantly inhibited to pulmonary oedema with a dose-dependent manner. The protective effect of morphine is prevented by peripheral opioid receptor antagonist, naloxone methiodide. ANTU-treated rats were shown positive by inducible nitric oxide synthase immunohistochemical staining. There was no staining in the control group. On the other hand, the degree of staining was markedly reduced in tissue sections by morphine. These results suggest that previous administration of subcutaneous morphine has preventive effect on ANTU-induced pulmonary inflammatory reaction and its effect mediated via peripheral opioid receptors. Application of naloxone with ANTU has no effect on the lung parameters indicating that endogenous opioids do not modulate ANTU-induced damage.

Topics: Animals; Dose-Response Relationship, Drug; Female; Immunohistochemistry; Lung; Male; Morphine; Naloxone; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Pulmonary Edema; Quaternary Ammonium Compounds; Rats; Thiourea

Aquaporins (AQPs) are water channel proteins that permit osmotically driven water movement. To determine their dynamics in pulmonary oedema, we examined the expression of mRNA and protein for AQP1, AQP3, AQP4, and AQP5 in the lungs of normal and thiourea-treated rats. In the thiourea group, lung water content increased significantly (vs. controls) with the peak at around 4 h. Semi-quantitative RT-PCR showed that AQP3 mRNA in the thiourea group rose significantly, peaking at around 4-8 h. The expression of AQP1, AQP4, AQP5, ENaC and CFTR mRNA each decreased significantly some time after the peak in lung water content. Immunoblot analysis showed that glycosylated AQP3 protein was increased 4-10 h after treatment. Expression of the other AQP proteins was not significantly altered, except for that of AQP4. Immunohistochemical examination revealed that AQP1 was expressed in endothelia, AQP3 in the basal cells of the large airways and in cuboidal cells in the bronchioles, AQP4 in the basolateral membrane of airway cells and AQP5 in type-I pneumocytes. Our results suggest that AQP3 is expressed not only in large airways, but also in bronchioles, and is related to water movement in pulmonary oedema.

Topics: Animals; Aquaporin 3; Aquaporins; Bronchi; Immunoblotting; Immunohistochemistry; Lung; Male; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Thiourea; Water

Oxidation of the low-density lipoprotein (LDL) results in the production of modified LDLs. Oxidation of LDL cholesterol plays a role on the pathogenesis of endothelial dysfunction. This study was designed to investigate the possible participation of the oxidative modification of low density lipoprotein in the lung edema induced by alpha-naphthylthiourea (ANTU), which is a well-known noxious chemical agent on the lung endothelium. When ANTU injected intraperitoneally into rats (15 mg kg(-1)), it produced lung edema as indicated by an increase in lung weight/body weight (LW/BW) ratio and pleural effusion (PE) reaching a maximum within 4 h. A significant lung edema was observed 4 h after intraperitoneally injection of alpha-naphthylthiourea when compared with olive oil-injected control rats. On microscopic examination of alpha-naphthylthiourea-treated rats were shown to have severe lung injury, while no change was observed in olive oil-treated control rats. While there were no staining in control lungs, positive oxidized low-density lipoproteins immune-fluorescent staining were observed in lung edema group. Our study showed that oxidized low-density lipoprotein (oxLDL) accumulated in ANTU-induced lung damage. This is the first study in which accumulation of oxLDL molecules in the intact lung tissue were shown by fluorescent immune-staining method in experimental lung edema. The potential role of oxLDL in this pathology are still under investigation.

Topics: Animals; Female; Lipoproteins, LDL; Lung; Male; Pulmonary Edema; Rats; Thiourea

This study was designed to investigate the possible participation of urethane, pentobarbital sodium and thiopental sodium anaesthesia in the lung oedema induced by alpha-naphthylthiourea (ANTU), which is a well known noxious chemical agent in the lung. ANTU when injected intraperitoneally (i.p.) into rats (10 mg x kg (-1) i.p.) produced lung oedema as indicated by an increase in lung weight/body weight (LW/BW) ratio and pleural effusion (PE) reaching a maximum within 4 h. Administration of urethane prior to ANTU, at doses of 100 and 200mg(100g)(-1), elicited a significant and dose-dependent inhibition in LW/BW ratio and PE. Thiopental sodium at doses of 25, 50 mg x kg (-1), also produced a significant and dose-dependent inhibition of both parameters. Prior i.p. injection of pentobarbital sodium at a dose of 40 mg x kg (-1) elicited a significant inhibition in both parameters. These results suggest that i.p. urethane, thiopental sodium and pentobarbital sodium pretreatment have a prophylactic effect on ANTU-induced lung injury in rats. The possible role of the anaesthetics in lung oedema induced by ANTU and the possible underlying mechanisms are discussed.

Topics: Animals; Hypnotics and Sedatives; Male; Organ Size; Pentobarbital; Pleural Effusion; Pulmonary Edema; Rats; Thiopental; Thiourea; Urethane

Neutrophil-derived oxygen free radicals have been implicated in the pathogenesis of noncardiogenic pulmonary edema. Fructose-1,6-diphosphate (FDP) has been shown to inhibit oxygen free radicals production by activated neutrophils. Thus, we investigated whether FDP would attenuate formation of pulmonary edema in anesthetized dogs injected with alpha-naphthylthiourea (ANTU). Hemodynamic studies involved measurements of left ventricular systolic and end-diasystolic pressures (LVSP and LVEDP), pulmonary artery pressure (PaP), heart rate (HR), and cardiac output (CO). Mean wet weight to dry weight ratios of lung tissue samples were calculated. Following baseline measurements, dogs were injected intravenously (IV) with ANTU 5 mg / kg (n = 16) and 10 mg / kg (n = 8) and half of the dogs were randomly selected to receive 75 mg / kg FDP (10%) and subsequent infusion of 7 mg / kg / min. The rest were given 0.9% NaCl in the same manner. Four hours after ANTU administration, the animals were euthanatized. Except for decline in the CO (nonsignificant), no significant changes in systemic hemodynamics within and between the groups were noted. In the FDP group, PaP and pulmonary arteriolar resistance (PaR) remained unchanged. In the saline group, PaP increased from 12.5 +/- 2.44 to 21.8 +/- 3.14 mm Hg (P < .001) and PaR from 166 +/- 29 to 468 +/- 74 dynes. cm / sec(5) (P < .005). During the study LVDEP, PaO(2), PaCO(2), and hematocrit did not change significantly within and between the groups. The lungs mean wet weight to dry weight ratios for the sham-operated dogs were 4.20 +/- 0.41, for the FDP group 4.32 +/- 0.59 and 6.22 +/- 1.37 for the saline group (P < .0005). These data indicate that FDP protected the lung from ANTU-induced injury.

Topics: Animals; Dogs; Drug Administration Schedule; Fructosediphosphates; Infusions, Intravenous; Injections, Intravenous; Pulmonary Edema; Rodenticides; Thiourea

Intravenous amphetamine abuse may cause serious cardiopulmonary complications via unknown mechanisms. We investigated the role of free radicals in the amphetamine-induced lung injury using isolated rat lungs. Adding amphetamine into the perfusate caused dose-dependent increases in perfusion pressure and lung weight. Amphetamine increased the filtration coefficient (K(f)) by 90 +/- 20% and 210 +/- 10% at doses of 10 microM and 50 microM, respectively, as compared to the baseline level. Pretreatment with dimethylthiourea (DMTU), an oxygen radical scavenger, abolished the pulmonary hypertension, lung weight gain, and permeability changes. We also examined the effect of amphetamine on free radical generation in polymorphonuclear leukocytes (PMN). Adding phorbol myristate acetate (PMA, 1 nM) enhanced the chemiluminescence indicating the functional viability of the isolated PMN. Amphetamine (50 microM) significantly enhanced the chemiluminescence generation of PMN by 152 +/- 26% as compared with the baseline value. Combination of amphetamine and PMA increased free radical formation by 360 +/- 85%. In summary, our results showed that amphetamine may cause acute lung injury by overproduction of free radicals. Although amphetamine can activate PMN, the source of free radicals remains to be determined.

Topics: Acute Disease; Animals; Blood Vessels; Capillary Permeability; Dextroamphetamine; Free Radical Scavengers; Free Radicals; In Vitro Techniques; Luminescent Measurements; Lung; Male; Neutrophils; Organ Size; Pulmonary Circulation; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Thiourea

The hypothesis that the changes in the respiratory system pressure- volume (PV) curve during pulmonary edema mainly reflect distal airway obstruction was investigated in rats. Normal rats had a well-defined upper inflection point (UIP) at low airway pressure. Airway occlusion by liquid instillation decreased compliance (Crs) and the volume (Vuip) of the UIP, and increased end-inspiratory pressure. The same changes were observed during the progression of edema produced by high volume ventilation (HV). Changes in Vuip and in Crs produced by HV were correlated with edema severity in normal rats or rats with lungs preinjured with alpha-naphthylthiourea. Vuip and Crs changes were proportional, reflecting compression of the PV curve on the volume axis and suggesting reduction of the amount of ventilatable lung at low airway pressure. In keeping with this explanation, the lower Vuip and Crs were before HV, the more severe HV-induced edema was in alpha-naphthylthiourea-injected rats. When edema was profuse, PV curves displayed a marked lower inflection point (LIP), the UIP at low pressure disappeared but another was seen at high volume above the LIP, and the correlation between Vuip changes and edema severity was lost. These observations may have clinical relevance in the context of the "open lung" strategy.. ventilator-induced lung injury; respiratory mechanics; acute respiratory distress syndrome

Topics: Airway Resistance; Animals; Disease Models, Animal; Inspiratory Capacity; Lung Compliance; Lung Volume Measurements; Male; Predictive Value of Tests; Pulmonary Edema; Rats; Rats, Wistar; Regression Analysis; Respiration, Artificial; Respiratory Distress Syndrome; Severity of Illness Index; Thiourea

Aquaporin (AQP) water channels provide a major pathway for osmotically driven water movement across epithelial and microvascular barriers in the lung. We used mice deficient in each of the three principal lung aquaporins, AQP1, AQP4 and AQP5, to test the hypothesis that aquaporins are important in neonatal lung fluid balance, adult lung fluid clearance and formation of lung oedema after acute lung injury. Wet-to-dry weight ratios (W/D) in lungs from wild-type mice decreased from 7.9 to 5.7 over the first hour after spontaneous delivery. AQP deletion did not significantly affect W/D at 45 min after birth. Alveolar fluid clearance was measured in living ventilated mice in which 0.5 ml saline containing radiolabelled albumin was instilled into the airspaces. Fluid clearance was 17.4 % in 15 min and inhibited >90 % by amiloride, but clearance was not affected by AQP deletion. W/D was measured in established models of acute lung injury - acid aspiration and thiourea administration. Two hours after intratracheal administration of HCl, W/D increased from 3.7 to 7.5 but was not affected by AQP deletion. Three hours after intraperitoneal infusion of thiourea, W/D increased to 5.5 and marked pleural effusions appeared, but there were no differences in wild-type and AQP knockout mice. Hyperoxic subacute lung injury was induced by 95 % oxygen. Neither mean survival (143 h) nor W/D at 65 h (5.1) were significantly affected by AQP deletion. Despite their role in osmotically driven lung water transport, aquaporins are not required for the physiological clearance of lung water in the neonatal or adult lung, or for the accumulation of extravascular lung water in the injured lung.

Topics: Acids; Age Factors; Animals; Animals, Newborn; Aquaporin 1; Aquaporin 4; Aquaporin 5; Aquaporins; Body Fluids; Hyperoxia; Indicators and Reagents; Membrane Proteins; Mice; Mice, Knockout; Pleural Effusion; Pulmonary Alveoli; Pulmonary Edema; Respiration, Artificial; Thiourea; Water-Electrolyte Balance

This study was designed to investigate the possible participation of the L-arginine-nitric oxide (NO) pathway in the lung oedema induced by alpha-naphthylthiourea, which is a well-known noxious chemical agent in the lung. Lung oedema was assessed by measuring fluid accumulation in the pleural cavity and the lung weight/body weight ratio following alpha-naphthylthiourea injection. Administration of NG-nitro-L-arginine methyl ester, a NO synthase inhibitor, prior to alpha-naphthylthiourea, produced a significant inhibition of pleural effusion and lung weight/body weight ratio in a dose-dependent manner. L-Arginine, but not D-arginine, when used higher doses (above 300 mg/kg) prior to alpha-naphthylthiourea injection caused a significant inhibition of pleural effusion without altering lung weight/body weight ratio. Lower doses of L-arginine (below 100 mg/kg) did not elicit an inhibitory effect against alpha-naphthylthiourea-induced pulmonary damage. However, lower doses of L-arginine greatly potentiated the inhibitory effect of NG-nitro-L-arginine-methyl ester against alpha-naphthylthiourea-induced lung oedema when used in combination. The interesting aspect of this study is the inhibition by NG-nitro-L-arginine methyl ester, a NO synthase inhibitor, and L-arginine, an endogenous donor of NO, of the lung oedema induced by alpha-naphthylthiourea. The possible role of the L-arginine-NO pathway in lung oedema induced by alpha-naphthylthiourea and the possible underlying mechanisms are discussed.

Topics: Animals; Arginine; Drug Synergism; Enzyme Inhibitors; Female; Lung; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Pleural Effusion; Pulmonary Circulation; Pulmonary Edema; Rats; Stereoisomerism; Thiourea

Keratinocyte growth factor (KGF) prevents alpha-naphthylthiourea (ANTU)-induced permeability edema ex vivo. To explore the mechanisms in this involved effect, we administered KGF (5 mg/kg, intratracheally) 48 h prior to ANTU (50 mg/kg, intraperitoneally). Several groups were studied: phosphate-buffered saline/dimethylsulfoxide (PBS/DMSO) (vehicles), PBS/ANTU, and KGF/ANTU. At 90 min after ANTU injection the lungs were removed, ventilated, and perfused ex vivo for 180 min. Quantification of fluorescein isothiocyanate (FITC)-labeled dextran in bronchoalveolar lavage fluid (BALF) was used to assess alveolar capillary barrier permeability. KGF attenuated ANTU-induced edema and blockade of sodium transport, with ouabain (10(-3) M) or amiloride (10(-4) M) added ex vivo reversed this effect. FITC-dextran was increased in the PBS/ANTU group as compared with the PBS/DMSO group, indicating permeability edema. In the KGF/ANTU group, there was concentration of BALF FITC-dextran, consistent with permeability edema and increased alveolar fluid export. Albumin space measurements showed similar increases in permeability in the PBS/ANTU and KGF/ANTU groups. Extravascular lung water (measured with radiolabeled erythrocytes) was decreased in the KGF/ANTU group. Following KGF pretreatment, uninjured lungs exported more intratracheal PBS than normal lungs following terbutaline stimulation ex vivo. In conclusion, KGF, through type II alveolar pneumocyte hyperplasia with increased sodium-potassium-adenosine triphosphatase (Na,K-ATPase) activity, attenuated ANTU-induced edema formation by potentiating alveolar fluid clearance.

Topics: Absorption; Amiloride; Animals; Biological Transport; Bronchoalveolar Lavage Fluid; Capillary Permeability; Dimethyl Sulfoxide; Enzyme Activation; Extravascular Lung Water; Fibroblast Growth Factor 10; Fibroblast Growth Factor 7; Fibroblast Growth Factors; Growth Substances; Ouabain; Pulmonary Alveoli; Pulmonary Edema; Rats; Sodium; Sodium Chloride; Sodium-Potassium-Exchanging ATPase; Thiourea

To investigate the effect of pretreatment with keratinocyte growth factor on acute permeability pulmonary edema.. Prospective, randomized, controlled animal study.. University research laboratory.. Specific pathogen-free Sprague-Dawley rats.. Acute permeability pulmonary edema was induced with an injection of alpha-naphthylthiourea, and lung leak was assessed in an isolated perfused lung model over 180 mins. Leak was confirmed with wet/dry lung weight ratios, and the alveolar fluid protein concentration was measured after bronchoalveolar lavage. The effect of pretreatment with keratinocyte growth factor (injected intratracheally 48 hrs before the experiment) on alpha-naphthylthiourea-induced pulmonary edema was assessed (keratinocyte growth factor/alpha-naphthylthiourea group). Control groups (Control and keratinocyte growth factor/Control) were also studied. Histopathology was performed for each of the four groups.. The alpha-naphthylthiourea produced an acute permeability pulmonary edema detected by lung leak over the 180-min ex vivo period of monitoring the isolated perfused lung (leak = 8+/-mL; wet/dry weight ratio 14.7+/-2; lavage protein 3.1+/-1 mg/mL). Pretreatment with keratinocyte growth factor significantly attenuated these parameters (leak = 2.3+/-0.4 mL; wet/dry weight ratio 7.1 +/- 0.5; lavage protein 0.28 +/-0.03 mg/mL), which were not significantly different from the control group and the keratinocyte growth factor/control group. Histopathology showed abundant type II pneumocyte hyperplasia in the lungs of animals pretreated with keratinocyte growth factor, and marked pulmonary edema in animals pretreated with alpha-naphthylthiourea. Less edema was apparent in the keratinocyte growth factor/alpha-naphthylthiourea group. All data are expressed as mean +/- SEM.. Pretreatment with keratinocyte growth factor significantly attenuates pulmonary edema induced by alpha-naphthylthiourea. The mechanisms of this protection are likely related to type II pneumocyte hyperplasia, but remain to be specifically elucidated.

Topics: Animals; Bronchoalveolar Lavage Fluid; Fibroblast Growth Factor 10; Fibroblast Growth Factor 7; Fibroblast Growth Factors; Growth Substances; Organ Size; Prospective Studies; Pulmonary Edema; Pulmonary Wedge Pressure; Random Allocation; Rats; Rats, Sprague-Dawley; Rodenticides; Thiourea

Alpha-naphthylthiourea when injected intraperitoneally to rats (10 mg kg-1 i.p.) produced lung oedema as indicated by an increase in lung weight/body ratio and pleural effusion reaching a maximum within 4 hours. Prior intravenous single bolus injection of endothelin-1 elicited a significant and dose-dependent inhibition in both parameters. However, prior i.v. injection of angiotensin II using relatively higher doses did not alter the oedema-producing effect of alpha-naphthylthiourea indicating a characteristic for endothelin-1. The inhibitory effect of endothelin-1 on pleural effusion is more prominent than lung weight/body weight ratio. The resolution of lung oedema by single bolus i.v. injection of endothelin-1 is probably due to the acute long-lasting and potent vasoconstrictor effect of the peptide and its large accumulation in lung tissue. Phosphoramidon, an inhibitor of endothelin converting enzyme, did not alter the oedema producing effect of alpha-naphthylthiourea indicating the lack of the participation of endothelin-peptide cascade to this pathological event. Bosentan, a non-selective receptor blocker of endothelin-1, did not inhibit the preventive effect of the peptide against alpha-naphthylthiourea-induced lung oedema. Possible mechanisms of the acute effect of endothelin-1 on lung oedema are discussed.

Topics: Angiotensin II; Animals; Aspartic Acid Endopeptidases; Body Weight; Bosentan; Endothelin-1; Endothelin-Converting Enzymes; Glycopeptides; Male; Metalloendopeptidases; Organ Size; Pleural Effusion; Protease Inhibitors; Pulmonary Edema; Rats; Sulfonamides; Thiourea

Previous studies have suggested that recovery from pulmonary edema may be dependent on active sodium ion transport. Most of the data supporting this concept came from work done in isolated type II cells, isolated lung preparations, or in models of alveolar flooding. There is a limited amount of information regarding the role of active sodium ion transport in vivo. Furthermore, most of this information was obtained in one model of pulmonary edema, the hyperoxic lung injury model. The purpose of these experiments was then to measure the activity of the sodium-potassium-adenosinetriphosphatase (Na(+)-K(+)-ATPase), the active component of the sodium transport process and an indirect marker of active sodium transport, during recovery from thiourea-induced pulmonary edema in rats. Na(+)-K(+)-ATPase activity was significantly increased during recovery from lung edema. This increase could not be accounted for by the Na(+)-K(+)-ATPase activity present in inflammatory cells recruited in the lung by the injury process or by a direct impact of thiourea on the enzyme. Alveolar flooding, induced by instillation of a protein-containing solution into the airways of ventilated rats also increased the activity of Na(+)-K(+)-ATPase, suggesting that activation of the enzyme is probably secondary to either the presence of edema or the physiological consequences associated with edema. The quantity of lung Na(+)-K(+)-ATPase protein was also elevated during edema resolution, indicating that augmented synthesis of this enzyme underlies the increased enzyme activity observed. The quantity of Na(+)-K(+)-ATPase protein in alveolar type II cells was also significantly enhanced during recovery from edema, suggesting that these cells contribute to active sodium transport in vivo. The results of this study suggest that active sodium transport could participate in the resolution of pulmonary edema.

Topics: Animals; Cells, Cultured; Lung; Male; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Sodium-Potassium-Exchanging ATPase; Thiourea

The modulatory role of histamine H3 receptors in pulmonary oedema induced by acetylcholine, capsaicin and by exogenous substance P was investigated in isolated, ventilated rabbit lungs. Endothelial permeability was evaluated by measuring the capillary filtration coefficient (Kf,c). Acetylcholine (10(-8) to 10(-4) M), substance P (10(-10) to 10(-6) M), capsaicin (10(-4) M) and 5-hydroxytryptamine (5-HT) (10(-4) M) induced an increase in the Kf,c. Carboperamide, a novel histamine H3 receptor antagonist, induced a significant leftward shift of the concentration-response curve to acetylcholine and also enhanced the effect of capsaicin on the Kf,c, while it had no significant effect on the response to substance P and 5-HT. Imetit, a new histamine H3 receptor agonist, strongly inhibited the effects of acetylcholine and capsaicin. Imetit also strongly protected the lung against substance P effects but did not prevent the 5-HT-induced increase in the Kf,c. Carboperamide completely blocked the inhibitory effect of Imetit on the acetylcholine response. (R)-alpha-Methylhistamine, an other histamine H3 receptor agonist, had the same protective effect against acetylcholine response as Imetit. We conclude that histamine H3 receptors could protect the lung against acetylcholine- and capsaicin-induced oedema via a prejunctional modulatory effect on the C-fibres. However, since the response to exogenous substance P was also inhibited by histamine H3 receptor stimulation, the presence of such receptors at a postsynaptic level, probably on mast cells, was also suggested.

Topics: Acetylcholine; Animals; Capillary Permeability; Capsaicin; Dose-Response Relationship, Drug; Drug Interactions; Endothelium; Female; Histamine Agonists; Histamine Antagonists; Imidazoles; In Vitro Techniques; Lung; Male; Nerve Fibers; Piperidines; Pulmonary Edema; Rabbits; Receptors, Histamine H3; Serotonin; Substance P; Thiourea

alpha-Naphthylthiourea (ANTU) when injected intraperitoneally to rats at a dose of 10 mg/kg elicited lung oedema indicated by an increase in lung weight/body weight (LW/BW) ratio and pleural effusion. The injection of acetylsalicylic acid, which is a cyclo-oxygenase inhibitor, and BW 755C, a cyclo-oxygenase and lipoxygenase inhibitor, prior to ANTU produced a significant inhibition in pleural fluid accumulation without changing the LW/BW ratio. BW A4C, a selective 5-lipoxygenase inhibitor, however, caused a highly significant inhibition in pleural effusion and a slight but significant decrease in LW/BW ratio. Thromboxane A2 synthetase inhibitor, UK 38485, caused a slight but significant inhibition in pleural fluid accumulation without altering the LW/BW ratio. Iloprost, however, produced a slight but significant inhibition in the LW/BW ratio without reducing the pleural effusion rate. A significant decrease in angiotensin-converting enzyme (ACE) activity in the isolated perfused lungs of ANTU-treated rats was noted. This observation was thought to be an evidence of a functional alteration of the lung vascular endothelium. The possible role of eicosanoids in lung oedema induced by ANTU and the related mechanisms of decreased ACE activity are discussed.

Topics: Animals; Eicosanoids; Female; In Vitro Techniques; Lung; Male; Peptidyl-Dipeptidase A; Perfusion; Pulmonary Edema; Rats; Rats, Inbred Strains; Thiourea

In vagotomized rats, cerebral compression (CC) produced marked increase in arterial pressure and pulmonary hemorrhagic edema (PHE). We studied the effects of a vasodilator and an oxidant scavenger to delineate the role of hemodynamic and permeability factors in this type of neurogenic PHE. Infusion of sodium nitroprusside at a dose of 5 micrograms/kg/min significantly reduced the CC-induced pressor response by 14% and the lung edema by 41%. A dose of 10 micrograms/kg/min blocked the pressor response by 51%, and completely prevented the lung injury. Dimethylthiourea (DMTU), a potent scavenger for oxidants such as hydroxyl radical and hydrogen peroxide, in doses of 300 and 600 mg/kg was pretreated 15 min before CC. Although DMTU was shown to block the permeability lung damage caused by phorbol myristate acetate (a neutrophil activator), this agent did not exert any effect on the CC-induced pressor response and lung injury. The data indicate that granulocyte-mediated oxidants such as hydroxyl radical and hydrogen peroxide do not appear to be involved in this type of neurogenic lung pathology. The results support the concept that PHE induced by intracranial hypertension is initiated by hemodynamic changes in the systemic and pulmonary circulation. Hydrostatic effect plays a major role in this type of neurogenic lung pathology.

Topics: Animals; Blood Pressure; Brain; Catheterization; Dose-Response Relationship, Drug; Free Radical Scavengers; Nitroprusside; Oxidants; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Thiourea; Vasodilator Agents

Using lucigenin-enhanced chemiluminescence, isolated rat lungs perfused with physiological salt-Ficoll solution were studied to test whether phorbol myristate acetate (PMA)-induced lung injury was mediated by reactive oxygen species (ROS). PMA (0.03 micrograms ml-1) caused small but significant increases in lung ROS levels and pulmonary arterial perfusion pressure (Ppa) but did not induce lung oedema. PMA (0.15 micrograms ml-1) induced lung oedema with large increases in ROS production and Ppa. Superoxide dismutase (SOD) inhibited the increases in ROS, Ppa, and lung oedema. Catalase and dimethylthiourea inhibited lung oedema but did not attenuate the increases in ROS and Ppa entirely. Indomethacin attenuated lung oedema partially but did not inhibit the increases in ROS and Ppa. These data indicate that PMA-induced lung injury is dependent on PMA concentration and ROS are responsible for such lung injury. Thromboxane plays a minor role for PMA-induced lung injury. The different effects of oxygen radical scavengers suggest that different radical species contribute to the increased pulmonary vascular response and lung injury.

Topics: Acridines; Animals; Catalase; Indomethacin; Luminescent Measurements; Lung; Lung Diseases; Male; Pressure; Pulmonary Artery; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Superoxide Dismutase; Tetradecanoylphorbol Acetate; Thiourea

The protective effects of dimethylthiourea, a potent scavenger of hydroxy radical (.OH) and hydrogen peroxide, in experimental lung injury in large animals remain controversial. The present study was designed to determine whether dimethylthiourea can ameliorate the acute lung injury produced in dogs by phorbol myristate acetate. Six dogs were infused with dimethylthiourea (0.75 g/kg in saline) for 1.5 hrs, beginning 1 hr before an i.v. bolus injection of phorbol myristate acetate (17 micrograms/kg); six dogs received phorbol myristate acetate (17 micrograms/kg) alone; and six dogs were infused with saline alone. Hemodynamic changes, arterial oxygenation, and the development of lung edema were monitored for 4 hrs after phorbol myristate acetate injection to assess the extent of lung damage.. As compared with the dogs that received phorbol myristate acetate alone, the edematous lung damage was significantly reduced in those dogs that received dimethylthiourea as well as phorbol myristate acetate. In the dimethylthiourea-treated dogs, the lung wet/dry weight ratios were smaller (p less than .01); protein concentrations in lung lavage fluid were lower (p less than .01); the decrease in PaO2 was significantly reduced (p less than .01); and there were significant reductions in the alveolar-arterial oxygen tension difference (P[A-a]O2) (p less than .01) and shunt (Qsp/Qt) (p less than .05). Also, dimethylthiourea significantly lowered the increased mean pulmonary arterial pressure levels during the second half of the experiment.. These experimental data suggest that dimethylthiourea is capable of reducing the neutrophil-mediated lung injury produced by the release of hydroxy radical and/or hydrogen peroxide in dogs exposed to phorbol myristate acetate.

Topics: Acute Disease; Animals; Blood Gas Analysis; Dogs; Drug Evaluation, Preclinical; Female; Hemodynamics; Lung; Male; Pulmonary Edema; Random Allocation; Tetradecanoylphorbol Acetate; Thiourea; Time Factors

Adult male rats treated with a lethal edematogenic dose of thiourea (TU) (10.0 mg/kg, intraperitoneally) responded with significant elevations in plasma histamine, lung vascular permeability and 100% mortality over a subsequent 24-h period. When rats were pretreated with a small non-lethal dose of TU (0.5 mg/kg) and subsequently challenged with the lethal dose at 1, 4, 8, 16 and 32 days later, there was complete protection against death for at least 8 days and partial protection for an additional 24 days. This decrease in mortality correlated quite closely with reduced plasma histamine levels and diminished pulmonary vascular permeability. The results suggest that reduced exposure of the pulmonary vasculature to histamine may offer a partial explanation for tolerance to thiocarbamide compounds in the rat.

Topics: Animals; Capillary Permeability; Drug Tolerance; Histamine; Lung; Male; Pulmonary Edema; Rats; Rats, Inbred Strains; Thiourea

Eugenol, an extract of cloves, has been associated with pulmonary edema when inhaled from commercially available clove cigarettes. We tested the hypothesis that eugenol directly causes lung edema through oxidant-mediated mechanisms by infusing eugenol (0.1 and 1.0 mM) into isolated rabbit lungs perfused with a cell-free albumin and physiologic salt solution. We observed lung edema (1.0 mM) as demonstrated by increased lung weight gain and wet-to-dry lung weight ratios without alterations in mean pulmonary artery pressure. The oxygen metabolite scavengers catalase (1,000 U/ml) and dimethylthiourea (30 mM) attenuated lung edema. Instillation of dimethylurea, superoxide dismutase, or heat-inactivated catalase did not prevent lung edema formation. We conclude that eugenol causes lung edema in isolated lungs through oxidant-mediated mechanisms in the absence of circulating formed blood elements. Eugenol may be a valuable compound in the laboratory investigation of edemogenic disorders.

Topics: Animals; Blood Pressure; Catalase; Eugenol; In Vitro Techniques; Lung; Methylurea Compounds; Organ Size; Oxygen; Pulmonary Artery; Pulmonary Edema; Rabbits; Superoxide Dismutase; Thiourea

Inhibitors of cytochrome P450, such as SK&F 525-A, prolong the duration of xylazine-ketamine anesthesia and cause pulmonary edema (PE) and death in rats. To determine the cause of PE, Sprague-Dawley rats were given a single dose of xylazine (21 mg/kg, im) alone or in combination with ketamine (45 mg/kg, im) and/or SK&F 525-A (50 mg/kg, ip) and percentage lung to body weight (%LW/BW) ratios (as an indicator of PE) were compared. The results indicated that xylazine caused PE which was independent of ketamine and was enhanced by SK&F 525-A. Subsequently, it was determined that 42 mg/kg xylazine, im, is an optimal edemagenic dose. Xylazine (42 mg/kg, im) increased the %LW/BW ratio as compared to control. Pleural effusion (PLE) of various amounts was observed in 75% of the animals. The pleural fluid to serum protein ratio for xylazine was similar to that obtained for alpha-naphthylthiourea (5 mg/kg, ip). Extensive serous PLE and alveolar edema with hemorrhage were found at necropsy in xylazine-treated rats. Pretreatment with yohimbine (4.2 mg/kg), prazosin (20 mg/kg), tolazoline (20 mg/kg), yohimbine (4.2 mg/kg) plus prazosin (20 mg/kg), atropine (20 mg/kg), dimethyl sulfoxide (DMSO) (7.8 g/kg), allopurinol (50 mg/kg), superoxide dismutase (20,000 U/kg), catalase (20,000 U/kg), BW755C (50 mg/kg), ibuprofen (50 mg/kg), cystathionine (100 mg/kg) plus taurine (100 mg/kg) did not affect the %LW/BW ratio. PLE was increased by yohimbine, yohimbine plus prazosin, and allopurinol, reduced by DMSO, and not changed in other groups. The results indicate that xylazine caused increased-permeability PE characterized by rapid onset, cellular damage and protein-rich pleural fluid. PE may not be mediated by adverse cardiovascular effects of xylazine and oxygen radicals are possibly involved in its etiology.

Topics: Anesthetics; Animals; Blood Proteins; Dose-Response Relationship, Drug; Lung; Male; Pleura; Pulmonary Edema; Rats; Rats, Inbred Strains; Thiourea; Xylazine

The intraperitoneal administration of thiourea (TU) to mature male rats results in a significant increase in lung vascular permeability to Evans Blue dye (EBD). On the other hand, young, sexually immature rats are resistant to this effect. The increase in lung vascular permeability in response to TU in mature rats is associated with corresponding increases in lung and plasma histamine levels. The correlation of increases in lung and plasma histamine in response to TU is similar to that reported for ammonium salts which produce similar pulmonary edema.

Topics: Age Factors; Animals; Capillary Permeability; Histamine; Lung; Male; Pulmonary Edema; Rats; Rats, Inbred Strains; Thiourea

Acute pulmonary edema can be induced by phorbol myristate acetate (PMA). Oxygen radicals released from the neutrophils have been considered to play an important role in the pathogenesis of PMA-induced pulmonary edema. In the present experiment, we studied the effect of dimethylthiourea (DMTU) on PMA-induced pulmonary injuries in isolated perfused lungs of rats. DMTU is a potent scavenger of the hydroxyl radical and hydrogen peroxide. PMA infusion into the isolated lung increased pulmonary arterial pressure (delta PAP) by 37.8 +/- 3.9 mmHg. The lung weight gain (LWG) and lavage albumin concentration (LAC) amounted to 6.2 +/- 1.2 g and 102.0 +/- 22.9 mg/dl, respectively. DMTU (100 mM) pretreatment significantly reduced the PAP increase (delta PAP = 4.6 +/- 0.8 mmHg, p less than 0.001), LWG (0.3 +/- 0.1 g, p less than 0.01) and LAC (25.3 +/- 1.7 mg/dl, p less than 0.01). Additional in vitro experiments demonstrated that DMTU depressed the chemiluminescence released from neutrophils activated by PMA (17.9 +/- 2.6 mV.min to 2.6 +/- 0.5 mV.min, p less than 0.01). The results suggest that DMTU, a scavenger of toxic radicals, decreases the lung edema through both attenuation of pulmonary hypertension and protection of vascular permeability from PMA injury.

Topics: Acute Disease; Animals; Blood Transfusion, Autologous; Free Radicals; In Vitro Techniques; Leukocyte Count; Neutrophils; Organ Size; Pulmonary Edema; Rats; Rats, Inbred Strains; Tetradecanoylphorbol Acetate; Thiourea

The diamine, putrescine, and polyamines, spermidine and spermine, are low molecular weight organic cations with documented regulatory roles in cell growth and differentiation. Multiple lines of direct and indirect evidence suggest that these organic cations also may function in stimulus-response coupling processes regulating cellular injury and repair. For example, recent studies in monocrotaline-treated rats, hyperoxic rats, and in cultured pulmonary endothelial cells suggest that polyamines regulate pulmonary endothelial integrity and may thus participate in development and/or regression of acute edematous lung injury. To determine if the polyamines are involved in a well-characterized animal model of acute lung injury, the present experiments assessed the relation between changes in polyamine synthesis and development of edema in lungs from rats treated with alpha-naphthylthiourea (ANTU). ANTU caused dose- and time-dependent increases in the lung activity of the initial and rate-limiting enzyme in polyamine biosynthesis, ornithine decarboxylase (ODC) and in the lung contents of the polyamines putrescine, spermidine, and spermine. ANTU also caused dose- and time-dependent increases in the lung wet-to-dry weight ratio indicative of pulmonary edema formation. Changes in lung polyamine biosyntheic activity after ANTU did not relate temporally to changes in the lung wet-to-dry weight ratio: ODC activity was depressed during the 3-h period immediately following ANTU administration, a period when the wet-to-dry weight ratio was increasing, and markedly elevated at 18 h after ANTU administration when the wet-to-dry weight ratio had returned to control levels. Pretreatment of the animals with alpha-difluoromethylornithine, a highly specific inhibitor of ODC, failed to attenuate ANTU-induced increases in lung wet-to-dry weight ratio. These observations indicate polyamine synthesis is enhanced in rat lungs with ANTU-induced pulmonary edema but, unlike certain other models of lung injury and pulmonary edema, accumulation of polyamines probably is not essential for development of edematous lung injury. It is conceivable that in this animal model polyamines play a role in lung repair processes or some longer-term consequence of lung injury.

Topics: Animals; Eflornithine; Lung; Male; Models, Biological; Organ Size; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitors; Polyamines; Pulmonary Edema; Rats; Rats, Inbred Strains; Thiourea

Injection of phorbol 12-myristate 13-acetate (PMA) into polymorphonuclear leukocyte (PMN)-depleted, PMN cytoplast-repleted New Zealand White rabbits caused the development of acute lung injury in vivo. PMN cytoplasts are nucleus- and granule-free vesicles of cytoplasm capable of releasing toxic O2 radicals but incapable of releasing granule enzymes. PMN cytoplasts when activated by PMA reduced 66 +/- 12.7 nmol of cytochrome c compared with 2.6 +/- 0.7 nmol in their resting state and did not release a significant quantity of granule enzymes (P greater than 0.05). Injection of PMA into New Zealand White rabbits caused a significant decrease (P less than 0.05) in the number of circulating cytoplasts. Increases in lung weight-to-body weight ratios in PMA-treated rabbits (9.8 +/- 0.5 X 10(-3] compared with saline-treated rabbits (5.3 +/- 0.2 X 10(-3] were also noted. Levels of angiotensin-converting enzyme in lung lavage as well as the change in alveolar-arterial O2 ratio correlated with the numbers of cytoplasts in lung lavage (P = 0.001, r = 0.84 and P = 0.0166, r = 0.73, respectively). Albumin in lung lavage increased to 1,700 +/- 186 mg/ml in PMA-treated rabbits from 60 +/- 30 mg/ml in saline-treated rabbits. These changes were attenuated by pretreatment of rabbits with dimethylthiourea (DMTU). In vitro, cytoplasts were able to mediate increases in endothelial monolayer permeability. This was evidenced by increases in fractional transit of albumin across endothelial monolayers when treated with PMA-activated cytoplasts (0.08 +/- 0.01 to 0.28 +/- 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Bronchoalveolar Lavage Fluid; Cell Membrane Permeability; Chemotaxis, Leukocyte; Endothelium; Humans; Lung; Lung Diseases; Neutrophils; Peptidyl-Dipeptidase A; Pulmonary Edema; Rabbits; Superoxides; Tetradecanoylphorbol Acetate; Thiourea

Early onset neonatal GBS infection is associated with pulmonary hypertension, pulmonary edema, and arterial hypoxemia. Although the mechanisms underlying these cardiopulmonary disturbances are not completely understood, multiple lines of evidence suggest that inflammatory mediators may be involved. This study examined the actions of dimethylthiourea (DMTU), a relatively selective scavenger of hydroxyl radical, on GBS-induced pulmonary hypertension, arterial hypoxemia, and pulmonary edema formation in young piglets. Relative to control animals, intravenous infusion of GBS (10(8) organisms/kg/min for 60 min) provoked sustained increases in pulmonary arterial pressure (Ppa: +88%) and total pulmonary resistance (TPR: 128%). GBS infusion also was associated with profound decreases in arterial PO2 (-58%). Pulmonary edema was present in GBS-treated animals as evidenced by an 8.4% increase in the lung wet-to-dry weight ratio. After pretreatment with DMTU (0.75 g/kg administered intravenously over 30 min), GBS increased Ppa by 33% and TPR by only 16%. Similarly, after DMTU pretreatment GBS decreased arterial oxygen tension by only 12%. DMTU also limited the GBS-induced increase in lung wet-to-dry weight ratio to 2.6%. These findings demonstrate that DMTU attenuates GBS-induced pulmonary hypertension, pulmonary edema, and arterial hypoxemia and suggest that hydroxyl radicals play an important role in these cardiopulmonary disturbances.

Topics: Animals; Free Radicals; Hydroxides; Hydroxyl Radical; Hypertension, Pulmonary; Hypoxia; Pulmonary Edema; Streptococcal Infections; Streptococcus agalactiae; Swine; Thiourea

We previously demonstrated that in vivo reperfusion of a dog lung after 48 h of pulmonary arterial (PA) ischemia results in pulmonary edema with a significant infiltrate of polymorphonuclear leukocytes. We hypothesized that the injury resulted from production of hydroxyl radical by activated neutrophils. In the current study, we attempted to prevent the injury in both dogs and rabbits with dimethylthiourea (DMTU), a scavenger of hydroxyl radical. After 48 h of left PA occlusion in 18 dogs, DMTU was administered to 9 animals and 9 were not treated. The occlusion was then released, and the dogs were killed 4 h later. Reperfusion resulted in a drop in leukocyte count and left lung edema, but there was no difference between treated and untreated animals. The wet-to-dry ratios of the lungs in the treated group were 5.76 +/- 0.44 (SE) on the reperfused left side and 4.50 +/- 0.06 (P less than 0.05) on the right side. In the untreated groups the comparable ratios were 5.73 +/- 0.31 and 4.92 +/- 0.10 (P less than 0.05 for right vs. left). Histological examination revealed significant differences between the right and left lungs in the extent of intra-alveolar granulocytes and macrophages but did not reveal differences between the treated and untreated animals. To ensure that neither the model nor the lack of response to DMTU was species specific, we then developed a rabbit model of reperfusion edema.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Disease Models, Animal; Dogs; Hydroxides; Hydroxyl Radical; Ischemia; Leukopenia; Lung; Lung Injury; Macrophages; Neutrophils; Pulmonary Edema; Rabbits; Thiourea

Re-expansion pulmonary edema (RPE) has been attributed to decreased lung interstitial pressures from a variety of mechanisms. Because some recent studies have implicated mechanisms that increase microvascular permeability in RPE, we tested whether the edema were due to free radical generation during re-expansion and reoxygenation of the collapsed lung. We used a rabbit model of RPE to test the effects of intracellular (dimethylthiourea) or extracellular (catalase) oxygen metabolite scavengers. Allopurinol was administered separately to determine whether xanthine oxidase was an important source of superoxide in this model. Edema was quantitated both gravimetrically and histologically, and lung xanthine oxidase activity was measured using a sensitive fluorometric assay with pterin as substrate. The results suggest indirectly that OH. or H2O2 (derived from O2-) contribute to the well-documented increase in lung permeability in RPE because dimethylthiourea, dimethylthiourea plus catalase, or catalase alone inhibited the edema to various degrees. Further, we observed histologically that increased numbers of neutrophils were present in re-expanded lungs and that neutrophil infiltration appeared to be diminished by antioxidant administration. Allopurinol did not decrease the edema, because xanthine oxidase activity in rabbit lung tissue is extremely low. We speculate that free radical generation in lung tissue contributes to the pathogenesis of RPE, although reinitiation of lung perfusion and ventilation requires a rapid change in intrathoracic pressure.

Topics: Allopurinol; Animals; Catalase; Free Radicals; Lung; Male; Pulmonary Atelectasis; Pulmonary Edema; Rabbits; Thiourea; Xanthine Dehydrogenase; Xanthine Oxidase

Endotoxin injected intraperitoneally caused leucopenia and pulmonary oedema in rats. These effects were spontaneously reversed over the 28 h after the single dose of endotoxin. The pharmacokinetics of three substrates, 14C-sucrose, 3H-prostaglandin E2 (PGE2) and 3H-adenosine, were measured in perfused lungs isolated from rats at different times after treatment with endotoxin. The efflux kinetics of radiolabel derived from sucrose and adenosine were little affected, but that from PGE2 was markedly changed. The metabolism of PGE2 was also decreased. The change in PGE2 pharmacokinetics preceded the pulmonary oedema, but both pharmacokinetics and oedema returned to normal at the same time (28 h after endotoxin). It may be feasible to use PGE2 pharmacokinetics as a biochemical index for early warning of acute lung injury caused by sepsis.

Topics: Adenosine; Animals; Dinoprostone; Endotoxins; Half-Life; In Vitro Techniques; Lung; Male; Pulmonary Edema; Rats; Rats, Inbred Strains; Respiratory Distress Syndrome; Sucrose; Thiourea

We investigated the effect of phorbol myristate acetate (PMA) in isolated guinea pig lungs perfused with phosphate-buffered Ringer solution. Pulmonary arterial pressure (Ppa), pulmonary capillary pressure (Ppc), and change in lung weight were recorded at 0, 10, 25, 40, and 70 min. The capillary filtration coefficient (Kf), an index of vascular permeability, was measured at 10 and 70 min. The perfusion of PMA (0.5 x 10(-7) M) increased Ppa, Ppc, and lung weight at 70 min. The ratio of arterial-to-venous vascular resistance (Ra/Rv) decreased and the Kf did not change with PMA. The perfusion of the lung with 4 alpha-phorbol didecanoate (inactive toward the protein kinase C analogue of PMA) did not affect the lung. The inhibition of TxA2 synthase with dazoxiben inhibited the response to PMA. The inhibition of the 5-lipoxygenase with U-60257 and the SRS-A receptor antagonist FPL 55712 also prevented the response to PMA. The addition of superoxide dismutase (SOD), catalase, or SOD plus catalase (the enzymes that remove O.2 H2O2, and OH., respectively) did not prevent the PMA effect or the release of TxA2; however, dimethylthiourea (DMTU), a scavenger of OH., did prevent the response to PMA. The data indicate that PMA causes a neutrophil-independent increase in lung weight due to increases in Ppc mediated by TxA2 and SRS-A. The protective effect of DMTU may be due to the inhibition of TxA2 generation.

Topics: Animals; Blood Pressure; Capillary Permeability; Female; Guinea Pigs; Male; Papaverine; Perfusion; Pulmonary Edema; SRS-A; Tetradecanoylphorbol Acetate; Thiourea; Thromboxane A2; Vascular Resistance

We compared areas and diameters of small airways and arteries in three groups of anesthetized dogs: 1) control (n = 5), 2) hydrostatic edema induced by fluid overload (n = 13), and 3) increased permeability edema induced with alpha-naphthylthiourea (n = 5). We measured pulmonary arterial and wedge pressures in all groups and cardiac output in the hydrostatic edema group. Postmortem, lobes were frozen at functional residual capacity and samples taken for measurements of extravascular lung water (Qwl/dQl) and for light microscopy. We also examined lobes from hydrostatic edema experiments fixed at transpulmonary pressures of 5 and 27 cmH2O. From the histology slides, bronchovascular bundles with respiratory bronchioles (n = 706) and bronchioles (n = 467) were photographed and airway and vessel areas and diameters measured. Alveolar and airway luminal edema were graded. We found that only in hydrostatic edema, pulmonary arterial and wedge pressures increased and vascular resistance fell with fluid infusion. Mean Qwl/dQl values were 3.80 +/- 0.17, 6.81 +/- 0.96, and 9.34 +/- 0.62 (SE) in control, hydrostatic, and increased permeability edema groups, respectively. By quantitative histology, airway and arterial areas and diameters did not decrease in edema and rose with increasing transpulmonary pressure. Variable quantities of air-space edema were seen. We conclude that interstitial edema does not compress small airways or arteries and that other mechanisms, including alveolar and airway luminal edema, may explain reported increases in airway resistance.

Topics: Animals; Cardiac Output; Dogs; Female; Hemodynamics; Isotonic Solutions; Lung; Male; Pulmonary Artery; Pulmonary Edema; Pulmonary Wedge Pressure; Ringer's Lactate; Thiourea; Vascular Resistance

Lung injury and pulmonary edema were induced in rats after intraperitoneal injection of 10 mg/kg alpha-naphthylthiourea (ANTU). The time course of development of lung injury was assessed by the clearance of 99mTc-diethylenetriamine pentaacetate (99mTcDTPA) from the lung into the blood, the pharmacokinetics of tritiated prostaglandin E2 [( 3H]PGE2) in the isolated perfused lung, and by increase in the weight ratio (wet-to-dry) of lung. Two hours after ANTU administration, the clearance of 99mTcDTPA was significantly faster than in untreated animals and implied an increase in permeability of the alveolar-capillary barrier. This change preceded the increase in wet-to-dry weight ratio of lung, which was not significant until 5 h after ANTU administration. The pharmacokinetics of [3H]PGE2 were significantly altered after ANTU and these changes persisted beyond the time when both lung weight ratio and 99mTcDTPA clearance had recovered to normal values. We conclude that both 99mTcDTPA clearance and PGE2 pharmacokinetics change in ANTU-induced lung injury but with different time courses. In the progressive phase of lung injury due to ANTU, the early change in clearance of 99mTcDTPA suggests that an increased permeation of the alveolar capillary barrier by this small molecule precedes pulmonary edema due to an increased colloid permeability of the barrier. Abnormal metabolism in the pulmonary microvasculature persists when the permeability defect and edema have recovered.

Topics: Animals; Capillary Permeability; Dinoprostone; Kinetics; Lung; Male; Organ Size; Organometallic Compounds; Pentetic Acid; Prostaglandins E; Pulmonary Edema; Rats; Rats, Inbred Strains; Technetium Tc 99m Pentetate; Thiourea

The rate and sequence of interstitial and alveolar fluid removal from the lung after the occurrence of pulmonary edema were examined. Rats were given intraperitoneal injections of 20 mg/kg alpha-naphthylthiourea (ANTU), resulting in an increased permeability edema with alveolar flooding. Animals were killed at intervals between 2 and 48 hours after ANTU for the gravimetric determination of extravascular lung water (Qwl/dQl) and histologic study of the lung. Interstitial fluid volume was quantified by a morphometric technique. The assumptions were made that edema fluid equaled the experimental Qwl/dQl minus the normal Qwl/dQl, and that the edema fluid volume equaled the sum of interstitial and alveolar fluid volume. It was found that between 2 and 4 hours after the induction of pulmonary edema, fluid was removed from the alveolar space faster than it was removed from the interstitial space. Between 4 and 48 hours after ANTU, the fluid removal rate from both compartments was much slower, and interstitial fluid was removed at a faster rate than alveolar fluid. It is hypothesized that the later phase of fluid removal from the lung is dependent on the removal of protein.

Topics: Animals; Biological Transport; Body Weight; Extracellular Space; Male; Pulmonary Alveoli; Pulmonary Edema; Rats; Thiourea; Time Factors

1 Pulmonary oedema, assessed by decreases in the lung dry weight:wet weight ratio, was induced in rats by a single i.p. injection of alpha-naphthylthiourea (ANTU). The oedema reached a peak at 4 h after ANTU and had completely resolved after 28 h. 2 Pulmonary pharmacokinetics of adenosine were measured in isolated, perfused lungs using radiolabelled adenosine and sucrose, injected into the perfusate as a single bolus. 3 By 1 h after ANTU the 1 min efflux of tracer for adenosine increased to over 60% and remained high until 16 h after ANTU. The time for 50% of injected radioactivity to appear in lung effluent (t1/2) for adenosine was reduced from its normal value of greater than 120 s to a minimum of 27 s at 1 h after ANTU. The proportion of adenosine in lung effluent did not change until 16 h after ANTU treatment but returned to normal by 50 h. 4 There were only minimal changes in the T1/2 and 1 min efflux for sucrose following ANTU treatment. 5 It appears that both the uptake and metabolism of adenosine are affected by ANTU-induced lung damage. The early effects are chiefly on uptake with metabolism remaining normal. Later (after 16 h) metabolism is decreased with uptake recovering to normal levels. 6 The effects on adenosine uptake paralleled the development and the resolution of oedema, suggesting that this variable might provide a biochemical index of the physical processes leading to lung oedema.

Topics: Adenosine; Animals; Chromatography, Thin Layer; Lung; Male; Permeability; Pulmonary Edema; Rats; Thiourea

Drugs possessing membrane stabilizing activity might act to diminish the augmented microvascular permeability resulting from acute lung injury. To test this rats were pretreated with quinidine, procainamide, or lidocaine and then given the lung injury-inducing agent thiourea. Vascular permeability, assessed as the extravascular accumulation of radiolabeled protein, was increased more than threefold by thiourea. This increase was diminished by 29, 34, and 43% after pretreatment with procainamide, quinidine, and lidocaine, respectively. Lidocaine also returned the thiourea-induced increase in lung wet weight-to-dry weight ratios to control levels. This protection was not likely due to hemodynamic effects of these agents, since no differences were noted in cardiac output between pretreated rats and those receiving thiourea alone and a small increase in mean pulmonary arterial pressure in the lidocaine-pretreatment group was the only difference noted. O2 metabolites have been implicated in the pathogenesis of thiourea-induced lung injury. None of these agents scavenged O2- or H2O2 directly, but quinidine and procainamide diminished in vitro neutrophil O2- and H2O2 production, and lidocaine inhibited neutrophil H2O2 production. However, neutropenia (PMN less than 100/ml) induced with either vinblastine or cyclophosphamide (Cytoxan) failed to prevent thiourea-induced increases in pulmonary vascular protein leak. In conclusion, procainamide, quinidine, and lidocaine diminished lung injury in rats after thiourea. Although these agents diminish PMN O2 metabolite production in vitro their salutary role in thiourea-induced lung injury appears to be through an unknown mechanism that is independent of their effects on neutrophil O2 metabolite-dependent toxicity.

Topics: Animals; Anti-Arrhythmia Agents; Capillary Permeability; Hemodynamics; Hydrogen Peroxide; In Vitro Techniques; Lidocaine; Lung; Male; Neutrophils; Organ Size; Procainamide; Proteins; Pulmonary Edema; Quinidine; Rats; Rats, Inbred Strains; Thiourea

Recent work with isolated blood vessels has emphasized the importance of intact endothelium when the relaxation of vascular smooth muscle is induced by acetylcholine (ACh). However, the physiologic significance of this endothelial-dependent ACh response in a complete organ circulation is unclear. We questioned whether diminished ACh vasodilation would result from damage of lung vascular endothelium and whether this response could be used as an indication of endothelial injury. We therefore induced pulmonary endothelial cell injury in one rat model by repeated injections of alpha-naphthyl thiourea (ANTU) and in a second rat model by exposing rats for 52 h to 100% oxygen at a barometric pressure of 760 torr (hyperoxia). Rats injected with Tween 80, the solvent for ANTU, or exposed to ambient Denver air served as the respective control animals. The isolated lungs of these rats were perfused with a recirculating cell- and plasma-free, physiological salt solution to study the effect of ACh or NaCl infusion on pulmonary perfusion pressure and vascular responsiveness. ANTU-treated rats demonstrated an intact vasodilatory response after ACh infusion when compared with the solvent control animals. The immediate pulmonary vasodilation after ACh infusion was slightly enhanced in the hyperoxic rat lung when compared with the rats exposed to ambient air, but there was no difference between these groups in the prolonged depression of vascular responsiveness to hypoxia or angiotensin II. Thus, in both models of lung endothelial cell injury, the pulmonary vascular responses to ACh were intact.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetylcholine; Acute Disease; Animals; Chronic Disease; In Vitro Techniques; Lung Diseases; Male; Microbial Collagenase; Microscopy, Electron; Oxygen; Perfusion; Pulmonary Circulation; Pulmonary Edema; Rats; Rats, Inbred Strains; Thiourea; Vascular Diseases; Vasodilation

alpha-Naphthylthiourea (ANTU) causes pulmonary edema and pleural effusion in rats. It has been suggested that ANTU pneumotoxicity may be mediated by blood neutrophils (PMNs) via the release of reactive oxygen species. Accordingly, we tested the effect of technical grade ANTU (tANTU) on the ability of rat peritoneal PMNs to release superoxide (O2-). tANTU did not itself stimulate O2- production by PMNs, but it increased the O2- released in response to PMN stimulation by phorbol myristate acetate (PMA). This effect was dependent upon the amount of tANTU added. In PMNs activated in vitro by a submaximal PMA stimulus, addition of 20 micrograms/ml tANTU doubled superoxide release. When tANTU was recrystallized from ethanol, the purified ANTU was not effective in potentiating the effect of PMA on PMNs. This suggests that an impurity in technical grade ANTU is capable of increasing O2- release by stimulated PMNs. tANTU and recrystallized ANTU caused similar pneumotoxicity in rats in vivo, suggesting that the unidentified impurity does not markedly influence the biologic effects of ANTU.

Topics: Animals; Drug Contamination; Drug Synergism; In Vitro Techniques; Male; Neutrophils; Pleural Effusion; Pulmonary Edema; Rats; Superoxides; Tetradecanoylphorbol Acetate; Thiourea

Treatment with dimethylthiourea (DMTU), a potent O2 metabolite scavenger, prevented neutrophil-mediated acute edema in lungs of rabbits given phorbol myristate acetate (PMA) and in isolated rabbit lungs perfused with neutrophils and PMA. DMTU-treated rabbits given PMA did not increase their lung weight-to-total body weight ratios (5.0 +/- 0.3) or lung lavage albumin concentrations (14 +/- 4.6 mg/dl) in comparison to untreated rabbits given PMA (6.6 +/- 0.5 and 60 +/- 10 mg/dl, respectively). Similarly, DMTU-treated isolated rabbit lungs perfused with neutrophils and PMA did not gain weight (0 g) or increase their lavage albumin concentrations (82 +/- 17 mg/dl) in comparison to untreated lungs perfused with neutrophils and PMA (71 +/- 3.1 g and 1,299 +/- 47 mg/dl, respectively). DMTU did not appear to decrease edema by preventing increases in pulmonary arterial pressures (PAP). First, treatment with DMTU did not decrease initial PAP increases in rabbits given PMA. Second, even though addition of DMTU attenuated PAP increases in isolated lungs perfused with neutrophils and PMA, DMTU-treated isolated lungs did not develop acute edema when subjected to mechanical increases in venous outflow pressures. The mechanism by which DMTU decreases lung edema is unclear but may involve scavenging of toxic O2 metabolites, since DMTU also decreased hydrogen peroxide (H2O2) and hydroxyl radical (OH) concentrations in in vitro mixtures containing neutrophils and PMA.

Topics: Acute Disease; Animals; Cell Count; Humans; In Vitro Techniques; Kinetics; Neutrophils; Perfusion; Phorbols; Pressure; Pulmonary Artery; Pulmonary Edema; Rabbits; Tetradecanoylphorbol Acetate; Thiourea

The detailed topography of filtration and of accumulation of the tracer dextran 75 was studied in 3 control dogs and in 9 experimental dogs in which edema was induced with 27 mg/kg alpha-naphthylthiourea. When moderately severe edema was present, 15-20 ml/kg of 6% dextran 75 was infused over 10-15 minutes; lung lobes were then fixed immediately by immersion, airway instillation, or vascular perfusion with 5% glutaraldehyde, 3% paraformaldehyde, or by freeze-substitution. For light microscopy, sections were embedded in methacrylate and stained with periodic acid-Schiff; for electron microscopy, they were embedded in Epon. The tracer was confined to the vasculature in controls. In all but one animal with edema, the tracer was seen in relation to capillaries, nonmuscular and partly muscular arteries, and veins, not in the walls of muscular arteries or around bronchial vessels. The dextran rapidly entered alveoli, lymphatics, and the interstitium around small vessels; there was much less tracer in the interstitium around larger vessels and essentially none around airways, consistent with the notion the interstitium acts as a sequestered pool. Furthermore, it was found that significant artifacts resulted from airway instillation and vascular perfusion fixation.

Topics: Animals; Capillary Permeability; Dextrans; Dogs; Female; Histological Techniques; Lung; Male; Microscopy, Electron; Pulmonary Alveoli; Pulmonary Edema; Thiourea

Even though dimethylthiourea (DMTU) effectively scavenges O2 metabolites in vitro, it is often unclear if scavenging of O2 metabolites is the mechanism by which DMTU decreases tissue injury in biological models. Since DMTU not only scavenges O2 metabolites but is also consumed in a dose-response manner following reaction with hydrogen peroxide (H2O2) in vitro, we wondered whether DMTU would also be consumed by O2 metabolites in biological systems and if DMTU consumption would then reflect O2 metabolite concentrations and O2 metabolite-mediated injury. Our results supported this possibility. We found that selected nonprotecting concentrations of DMTU were consumed in isolated rat lungs perfused with H2O2 and that the amounts of DMTU consumed reflected both the added amounts of H2O2 and the corresponding degrees of H2O2-induced acute edematous injury. DMTU consumption was relatively specific for reaction with H2O2 occurring in isolated lungs that were injured by H2O2 but not lungs injured by elastase, oleic acid, histamine, or a venous pressure challenge. Our results suggest that measurement of DMTU consumption may be useful for assessing the presence and toxicity of O2 metabolites and the specificity of the protective effects of DMTU in biological systems.

Topics: Animals; Carboxypeptidases; Hydrogen Peroxide; Male; Peptidyl-Dipeptidase A; Pulmonary Edema; Rats; Rats, Inbred Strains; Thiourea

We used the in situ blood-perfused left lower lobe preparation of the dog to examine the effect of hydrostatic and permeability edema on the slope and intercept of the vascular pressure-flow (P/Q) relationship and on the longitudinal distribution of vascular resistance with the arterial and venous occlusion technique. Hydrostatic edema (HE) was induced by raising the venous pressure, and permeability edema (PE) was induced with alpha-naphthylthiourea. When the hematocrit (Hct) of the perfusate was kept normal (approximately 40%), HE had no significant effect on either the slope or the intercept of the P/Q relationship or on the distribution of vascular resistance. PE caused a small increase in the intercept of the P/Q relationship and a small rise in the resistance of the vessels in the middle segment. In another series of HE experiments in which Hct was allowed to increase during edema formation, there was a marked increase in vascular resistance. We conclude that edema per se does not increase vascular resistance significantly and that the increases in vascular resistance which were observed previously by other investigators in the isolated lungs may be due to increases in blood hematocrit.

Topics: Animals; Blood Pressure; Dogs; Hematocrit; Hydrostatic Pressure; In Vitro Techniques; Pulmonary Circulation; Pulmonary Edema; Thiourea; Vascular Resistance

Noninvasive techniques employing external counting of radiolabeled protein have the potential for measuring pulmonary vascular protein permeability, but their specificity and sensitivity remain unclear. We tested the specificity and sensitivity of a double-radioisotope method by injecting radiolabeled albumin (131I) and erythrocytes (99mTc) into anesthetized dogs and measuring the counts of each isotope for 150 min after injection with an external gamma probe fixed over the lung. We calculated the rate of increase of albumin counts measured by the probe (which reflects the rate at which protein leaks into the extravascular space). To assess permeability we normalized the rate of increase in albumin counts for changes in labeled erythrocyte signal to minimize influence of changes in vascular surface area and thus derived an albumin leak index. We measured the albumin leak index and gravimetric lung water during hydrostatic edema (acutely elevating left atrial pressure by left atrial balloon inflation: mean pulmonary arterial wedge pressure = 22.6 Torr) and in lung injury edema induced by high- (1.0 g/kg) and low-dose (0.25 g/kg) intravenous thiourea. To test specificity we compared hydrostatic and high-dose thiourea edema. The albumin leak index increased nearly fourfold from control after thiourea injury (27.2 +/- 2.3 X 10-4 vs. 7.6 +/- 0.9 X 10-4 min-1) but did not change from control levels after elevating left atrial pressure (8.9 +/- 1.2 X 10-4 min-1) despite comparable increases in gravimetric lung water. To test sensitivity we compared low-dose thiourea with controls. Following low-dose thiourea, the albumin leak index nearly doubled despite the absence of a measurable increase in lung water. We conclude that a noninvasive double radioisotope measurement of pulmonary vascular protein leak, employing external counting techniques and a simplified method of calculation, is specific for lung injury and is also sensitive enough to detect lung injury insufficient to produce detectable pulmonary edema.

Topics: Animals; Blood Pressure; Blood Proteins; Capillary Permeability; Cardiac Output; Dogs; Iodoproteins; Lung; Pulmonary Edema; Serum Albumin; Technetium; Thiourea

Using the thiocarbamide model of acute lung injury in rats, we found that alpha-naphthylthiourea (ANTU) caused lung endothelial cell injury, as evidenced by increased permeability edema and decreased angiotensin I conversion. These effects were associated with enhanced pulmonary vascular reactivity. Recurrent ANTU lung injury caused pulmonary hypertension. The water-soluble thiocarbamide thiourea caused cultured vascular endothelial cells to release neutrophil chemoattractant activity. We speculate that endothelial cell injury may modulate the function of vascular smooth muscle and blood leukocytes.

Topics: Angiotensin II; Animals; Endothelium; Hypertension, Pulmonary; Lung; Lung Diseases; Male; Muscle, Smooth, Vascular; Neutrophils; Pulmonary Edema; Rats; Rats, Inbred Strains; Thiourea

Synthesis of COP (prostaglandins; PG and thromboxanes; Tx) from exogenous and endogenous arachidonic acid (AA) was studied in isolated perfused lungs from rats treated in vivo with a single dose of alpha-naphthylthiourea (ANTU; 10mg/kg;). Lung dry:wet weight ratios showed changes characteristic of oedema between 6 and 16h after ANTU. Bioassay of COP showed that COP synthesis from exogenous AA was raised above control values in lungs from rats treated with ANTU, reaching a maximum at 16h after treatment. By radioimmunoassay, the major increase was in 6-oxo-PGF1 alpha, with lesser effects on PGE2 and PGF2 alpha levels. Synthesis of bioassayable COP from endogenous AA induced by the calcium ionophore A23187 was increased as early as 2h after ANTU treatment and remained elevated up to 70h. In lungs 28h after ANTU, 6-oxo-PGF1 alpha release was greater than in normal lungs. These results show that in this model of pulmonary oedema, the potential for COP synthesis was increased. From the time course of this effect, increased COP synthesis was probably a response to the initial damage rather than a cause of the oedema.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Calcimycin; In Vitro Techniques; Lung; Male; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Pulmonary Edema; Rats; Rats, Inbred Strains; Thiourea; Thromboxanes

Topics: Animals; Dinoprostone; Half-Life; Kinetics; Lung; Male; Prostaglandins E; Pulmonary Edema; Rats; Thiourea; Thromboxane B2; Tritium

Toxic, partially reduced metabolites of oxygen (toxic oxygen radicals) are increasingly implicated in acute leukocyte-mediated tissue injury. To further probe the roles of oxygen radicals in acute lung edema, I studied the effects of a recently described and very potent oxygen radical scavenger, dimethylthiourea (DMTU) (Fox, R. B., R. N. Harada, R. M. Tate, and J. E. Repine, 1983, J. Appl. Physiol., 55:1456-1459) on polymorphonuclear leukocyte (PMN) oxidant function and on two types of lung injury mediated by oxygen radicals and PMN. DMTU (10 mM) blocked 79% of hydroxyl radical (OH) production by PMN in vitro without interfering with other PMN functions, such as O-2 production, myeloperoxidase activity, chemotaxis, degranulation, or aggregation. When isolated rat lung preparations were perfused with PMN activated to produce OH, lung weights were increased from 2.3 +/- 0.2 to 11.2 +/- 0.8 g. DMTU (10 mM) prevented 70% of these increases (lung weights, 5.0 +/- 1.1 g, P less than 0.005). Finally, when intact rats were exposed to 100% O2 for 66 h, lung weight:body weight ratios were increased from 5.78 +/- 0.33 to 8.87 +/- 0.16 g. DMTU (500 mg/kg) prevented 83% of this hyperoxia-induced lung edema in vivo (lung:body weight ratios, 6.05 +/- 0.21, P less than 0.001). Pharmacokinetic studies showed that DMTU diffused effectively into lung interstitial fluids and had a relatively long half-life (25-35 h) in the circulation. Because a variety of oxygen radicals, such as superoxide (O-2), hydrogen peroxide (H2O2), or OH are produced by PMN, there is usually some uncertainty about which one is responsible for injury. However, in these studies, DMTU did not scavenge O-2 and scavenged H2O2 only very slowly while scavenging OH very effectively. Therefore, DMTU may be useful in the investigation of the roles of oxygen radicals, especially OH, in acute granulocyte-mediated tissue injury.

Topics: Animals; Cell Aggregation; Chemotaxis, Leukocyte; Cytoplasmic Granules; Free Radicals; Humans; Hydrogen Peroxide; Hydroxides; Hydroxyl Radical; In Vitro Techniques; Kinetics; Lung; Lung Injury; Neutrophils; Oxygen; Pulmonary Edema; Rats; Rats, Inbred Strains; Superoxides; Thiourea

A controversy exists as to the preferred solution for plasma volume replacement and cardiac output maintenance in the presence of lung injury. To evaluate these responses, crystalloid and colloid infusions were compared in dogs treated with 5 mg/kg of alpha-naphthylthiourea (ANTU), which produces a predictable increase in vascular permeability and extravascular water (QW) in the lung. A tracheobronchial lymphatic from the left lung was cannulated and left atrial (Pla) pressure, lymph flow, lymph-to-plasma protein concentration ratios, and thermal dilution cardiac output were monitored. Test infusions were either 15 ml/kg of 6% dextran 70 (DX) or 60 ml/kg of normal saline (NS) infused over 20 min. Solutions were infused 3 h after ANTU as follows: group I (DX); group II (NS), group III (DX, constant Pla); and group IV (NS, constant Pla). In groups III and IV, Pla was maintained constant by bleeding into a reservoir during an exchange transfusion. Postinfusion QW increased to 9.01 and 9.14 g/g blood-free dry wt for groups I and II, respectively, but there was no significant postinfusion increase in QW for groups III and IV compared with the 3-h preinfusion values. However, cardiac output was significantly higher at 5 h in group III compared with group IV. These studies indicate that capillary hydrostatic pressure was the major determinant of QW during the infusions but that DX maintained cardiac output significantly higher because of vascular retention of the colloids.

Topics: Animals; Body Fluids; Capillary Permeability; Cardiac Output; Dextrans; Dogs; Hemodynamics; Infusions, Parenteral; Lymph; Pulmonary Edema; Thiourea

During routine inhalation toxicity studies, microscopic examination of tissues from lungs which have shown small, but statistically significant increases, in organ weight has failed to show evidence of any pathological change. Historically, increases, thought to be due to mild oedema, have been difficult to identify microscopically. A method suitable for dealing with large numbers of rodents has been developed, which can detect microscopically changes associated with small increases in lung weight. The lungs were inflated with formalin vapour and fixed in 10% buffered formalin. Histological processing methods were varied to obtain the best demonstration of oedema. Fixation methods were compared using alpha-naphthylthiourea-induced oedematous lungs. The left lobe was inflated with formalin vapour and the rest of the lung was distended with 10% buffered formalin. The best demonstration of oedema followed formalin vapour fixation. Evidence of oedema, indicated by lung weight increases of approximately 10%, was seen microscopically in formalin-vapour-fixed lungs, but was not seen in the lobes distended with 10% buffered formalin. Application of this technique to other species including cats and dogs has also proved successful.

Topics: Animals; Cats; Lung; Male; Organ Size; Pulmonary Edema; Rats; Rats, Inbred Strains; Staining and Labeling; Thiourea

alpha-Naphthyl thiourea ( ANTU ) produces pulmonary endothelial injury, pulmonary edema, and pleural effusions in rats in a dose-dependent manner. Since prostaglandins of the E series have been shown to modulate inflammatory responses in vivo and neutrophil and platelet function in vitro we investigated the effects of prostaglandin E1 (PGE1) on ANTU -induced lung injury. Systemic administration of 15-(S)-15-methyl-PGE1 (15-M-PGE1), a stable analog of PGE1, potentiated lung injury induced by ANTU in a dose- and time-dependent manner. 15-M-PGE1 (1 mg/kg, subcutaneously) administered 1 hour prior to ANTU treatment (1 mg/kg, intraperitoneally) resulted in a 164% increase (p less than 0.001) in pleural effusion formation and a 42% increase (p less than 0.02) in wet lung weight at 4 hours after ANTU administration. This was associated with increased pulmonary endothelial cell blebbing and gap formation with a decrease in the number of platelet thrombi in 15-M-PGE1-treated animals compared with controls. 15-(S)-15-methyl-prostaglandin F2 alpha, was less effective than 15-M-PGE1 in potentiating ANTU -induced lung injury. Platelet depletion, but not neutrophil depletion, also potentiated ANTU -induced lung injury, suggesting a protective role for platelets. Platelets isolated from 15-M-PGE1-treated animals demonstrated an approximately 50% decreased aggregation response to adenosine diphosphate. 15-M-PGE1 (1 mg/kg) treatment combined with platelet depletion resulted in a 1.7-fold increase (p less than 0.01) in pleural effusions in ANTU -treated (1 mg/kg) animals compared with platelet depletion alone. These studies indicate that systemic treatment of rats with 15-M-PGE1 will potentiate ANTU -induced lung injury. This injury may be in part secondary to the ability of 15-M-PGE1 to inhibit platelet function. However, platelet depletion studies suggest that 15-M-PGE1 has additional effects, possibly on endothelial cells and/or vascular smooth muscle cells that contribute to the potentiation of ANTU -induced lung injury.

Topics: Alprostadil; Animals; Blood Platelets; Dose-Response Relationship, Drug; Lung; Male; Microscopy, Electron; Pleural Effusion; Prostaglandins E, Synthetic; Pulmonary Edema; Rats; Rats, Inbred Strains; Rodenticides; Specific Pathogen-Free Organisms; Thiourea; Time Factors

Bilateral injection of the inhibitor of histamine-N-methyltransferase, SKF 91488, which is also known as homodimaprit (5 micrograms), into the preoptic area of the rat produced delayed hypertension, tachycardia and hyperthermia. Some animals exhibited pulmonary edema. These effects were only noted 18-24 hr after an injection and were not an artifact of the injection, since the administration of artificial cerebrospinal fluid produced none of these effects. At the time noted, lesions of the rostral hypothalamus, including the preoptic area, were evident. Injection of a vasopressin antagonist, intravenously, did not lower the blood pressure of the hypertensive animals nor did previous bilateral adrenal demullation prevent or delay the hypertension or tachycardia. Therefore, it does not appear that hypersecretion of either vasopressin or adrenal catecholamines contributed to the cardiovascular effects. Peripheral pretreatment with the sympathetic neurotoxin 6-hydroxydopamine however, did prevent the delayed rise in blood pressure following an injection of homodimaprit. From these studies, it is concluded that the injection of homodimaprit produces lesions in the preoptic area, resulting in hypertension that is maintained by excessive activation of the sympathetic nervous system.

Topics: Adrenal Medulla; Animals; Arginine Vasopressin; Blood Pressure; Body Temperature; Brain; Cerebrospinal Fluid; Dimaprit; Heart Rate; Hexamethonium Compounds; Histamine N-Methyltransferase; Hypothalamus; Male; Methyltransferases; Pulmonary Edema; Rats; Rats, Inbred Strains; Sympathectomy, Chemical; Thiourea

We utilized light microscopic morphometry to examine the distribution of fluid in bronchovascular bundles of different sizes. Permeability edema was induced in 10 anesthetized dogs with 27 mg/kg of alpha-naphthylthiourea. Eight dogs served as controls. After moderately severe edema, diagnosed on chest radiographs and with decreasing arterial pO2, lobes were fixed with glutaraldehyde and formaldehyde or by freeze substitution. Postmortem wet weight to dry weight ratios were 7.82 +/- 0.62 (mean +/- SE) in the edematous lungs and 4.38 +/- 0.25 in the controls. Bronchovascular bundles were photographed and grouped as follows: bundles composed of separated arteries and bronchioles, bundles with connected arteries and bronchioles, and bundles with connected arteries and bronchi. The transparencies were projected on a tablet interfaced to a computer and the following areas were determined: T, the total bundle area; V, the vessel (artery) area; B, the airway (bronchiole or bronchus) area; A1, the tight periarterial adventitial sheath area; A2, the loose periarterial interstitial area; and A3, the bronchiolar/bronchial interstitial area. In addition, edema ratios for arteries (A2/V) and airways (A3/B) were calculated. We found that (a) A1 was very small and did not change with edema; (b) A2 in all bundles increased 10-fold with edema (p less than 0.01), whereas A3 increased 2- to 3-fold; (c) A2/V increased 9- to 15-fold in the edematous bundles (p less than 0.01) and (d) A3/B did not change in separated bundles (p greater than 0.05) but was approximately double after edema in the connected bundles with bronchioles and bronchi (p less than 0.01). We conclude that edema in bronchovascular bundles accumulates preferentially in the loose periarterial interstitium and does not appear to accumulate around smaller bronchioles. These data may be explained by anatomical factors and by gradients of interstitial pressure.

Topics: Animals; Bronchi; Capillaries; Capillary Permeability; Dogs; Extracellular Space; Female; Male; Pulmonary Edema; Thiourea

alpha-Naphthylthiourea (ANTU) damages the pulmonary capillary endothelium producing a marked pulmonary edema. Since the pulmonary microvasculature regulates the circulating levels of serotonin (5-HT), the role of 5-HT in the pathophysiology of ANTU-induced pulmonary edema was examined. Mice treated with ANTU (10 mg/kg, ip) rapidly developed pulmonary edema which was maximal at 3 hr and was resolved by 12 hr. The lung content of both endogenous 5-HT and a tracer dose of 5-[3H]HT paralleled the time course of the development and resolution of the pulmonary edema. ANTU produced a significant thrombocytopenia (58 to 72%) at all time points, and an elevated platelet content of 5-HT and 5-[3H]HT during the resolution phase (6 to 12 hr). Drugs possessing select effects on 5-HT were shown to alter the edematogenic response to ANTU. Fluoxetine, a selective inhibitor of 5-HT uptake, potentiated the pulmonary edema, while clorgyline, an irreversible inhibitor of type A monoamine oxidase, was without effect. Reserpine which depletes 5-HT stores prevented both thrombocytopenia and pulmonary edema in response to ANTU. Reloading the lung and platelet 5-HT stores of reserpinized animals reestablished the normal response to ANTU. Pretreatment with the selective 5-HT2 receptor antagonist, ketanserin, prevented the thrombocytopenia, the increase in lung content of 5-HT and 5-[3H]HT, and prevented the edematogenic response to ANTU by 70%. These data indicate a major role for 5-HT in the pathophysiology of acute lung microvascular injury produced by ANTU.

Topics: Animals; Blood Platelets; Clorgyline; Drug Interactions; Fluoxetine; Ketanserin; Lung; Male; Mice; Piperidines; Pulmonary Edema; Reserpine; Serotonin; Serotonin Antagonists; Thiourea; Thrombocytopenia

Rat lungs were inflated and incubated in either anionic or cationic ferritin, and alveolar and capillary basement membranes were examined by electron microscopy. Cationic ferritin bound to heparan sulfate proteoglycans on the external surface of the alveolar basement membrane, whereas cationic ferritin bound to the lamina densa of the capillary basement membranes. Anionic and cationic ferritin was also perfused through the pulmonary circulation of lungs isolated from control rats and rats previously injected with alpha-naphthylthiourea, which produces permeability pulmonary edema. Neither anionic nor cationic ferritin leaked from the pulmonary capillaries in perfused controls; cationic, but not anionic, ferritin adhered to endothelial cell surfaces. In lungs with alpha-naphthylthiourea pulmonary edema, perfused for 2-15 minutes, anionic ferritin leaked from pulmonary capillaries into the alveolar interstitium and alveolar space, while cationic ferritin remained within the capillary lumen. Five times as much anionic ferritin appeared in the capillary basement membranes on the thick side of the alveolar wall, as in the alveolar basement membranes on the thin side of the alveolar wall. In alpha-naphthylthiourea lungs perfused for 45-60 minutes, cationic ferritin also leaked through the injured endothelium and bound twice as much to the alveolar as the capillary basement membranes. The negatively charged pulmonary capillary endothelium, the positively charged capillary basement membranes, and the negatively charged alveolar basement membranes may influence the transport of macromolecules from the pulmonary circulation in permeability pulmonary edema.

Topics: Animals; Basement Membrane; Biological Transport; Chondroitin Sulfate Proteoglycans; Ferritins; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Lung; Male; Microscopy, Electron; Perfusion; Permeability; Pulmonary Circulation; Pulmonary Edema; Rats; Rats, Inbred Strains; Thiourea; Tissue Distribution

To determine the effect of the type of lung injury on the thermodilution estimation of extravascular lung water, we produced pulmonary edema in 25 anesthetized dogs by injection of alloxan or alpha-naphthylthiourea (ANTU) into the pulmonary circulation or by instillation of hydrochloric acid (HCI) into the airway. HCl injury was bilateral, unilateral with tidal volume equal in each lung, or unilateral with equal airway pressure. Extravascular thermal volume (ETV) was measured at base line and 4 h after lung injury, and the final measurement was compared with the postmortem determination of extravascular lung mass (ELM). In 11 of 15 animals with HCl injury final ETV was less than the base-line measurement. The ratio of final ETV to ELM for all HCl animal (group I) averaged 0.31 +/- 0.14, which was different from the value for animals with alloxan or ANTU injury (group II), 1.04 +/- 0.14 (P less than 0.01). Extravascular lung water per gram of blood-free dry tissue was not different for the two groups (8.1 +/- 1.2 and 8.7 +/- 2.6 for I and II, respectively), indicating equally severe lung injury; however, shunt fraction was less in group I (P less than 0.01). ETV/ELM correlated with the shunt fraction for group I (r = 0.70) but not for group II (r = 0.32). These findings indicate that ETV underestimates lung water after HCl injury due to the redistribution of pulmonary blood flow away from edematous areas.

Topics: Alloxan; Animals; Cardiac Output; Dogs; Extracellular Space; Hydrochloric Acid; Lung; Pulmonary Circulation; Pulmonary Edema; Thermodilution; Thiourea; Tidal Volume

Topics: Animals; Body Water; Capillary Permeability; Catalase; Dogs; Lymph; Pulmonary Edema; Superoxide Dismutase; Thiourea

We investigated the effects of lung injury due to alpha-naphthylthiourea (ANTU) on pulmonary vascular reactivity. Rats were treated with ANTU (10 mg/kg ip) or the vehicle Tween 80. Four hours later, lungs from ANTU-treated rats had increased wet-to-dry weight ratios, bronchial lavage protein concentrations, and perivascular edema. To test vascular reactivity, lungs were isolated and perfused with blood at constant flow rate, while mean pulmonary arterial pressure was monitored. ANTU-treated lungs vasoconstricted earlier than Tween-treated lungs in response to severe airway hypoxia (fractional inspired O2 0%). ANTU-treated lungs vasoconstricted in response to 10% O2, while Tween-treated lungs failed to respond to 10% O2, indicating that the threshold for hypoxic vasoconstriction was decreased by ANTU. ANTU also decreased the threshold for and increased the magnitude of angiotensin II pressor responses, indicating that the increased vasoreactivity was not specific for hypoxia. Addition of meclofenamate to perfusates increased the rate and magnitude of responses to 0% O2 in Tween-treated lungs, but did not change the responses of ANTU-treated lungs. Light microscopy of ANTU-treated lungs showed no pulmonary arterial obstruction, and electron microscopy revealed mild capillary endothelial cell injury. We conclude that enhanced pulmonary vascular reactivity accompanies the increased-permeability pulmonary edema caused by ANTU. A similar increase in vasoreactivity might contribute to pulmonary hypertension observed in patients with the adult respiratory distress syndrome.

Topics: Angiotensin II; Animals; Blood Vessels; Hypoxia; Lung; Male; Meclofenamic Acid; Oxygen; Polysorbates; Pulmonary Circulation; Pulmonary Edema; Rats; Rats, Inbred Strains; Thiourea; Time Factors; Vasoconstriction

The time course of the respiratory consequences of alpha-naphthyl thiourea (ANTU)-induced lung oedema was studied in adult albino rats, up to 6 h after the injection of 5 mg/kg ANTU. Control rats were injected with olive oil (ANTU solvent). After 6 h, pulmonary extravascular water increased by 50% in ANTU-treated rats and the volume of the pleural effusion reached 3.4 +/- 0.1 ml (mean +/- s.e. mean). The most striking point is the absence of hypoxaemia in the ANTU-treated rats: PaO2 = 103 +/- 1.5 Torr vs 100 +/- 1 Torr in the control rats. The non-decreased PaO2 can be related to the patency of the alveolar airspaces. The predominant location of the oedema in the lung interstitium is caused by a specific lymphatic drainage pathway towards the pleura in the rat which prevents alveolar flooding. Histological findings support this hypothesis. PaCO2 is unaltered: 32 +/- 1 Torr in ANTU rats vs 33.5 +/- 1 Torr in control rats. A slight downward shift of arterial pH is found in ANTU rats: (7.440 +/- 0.010 vs 7.475 +/- 0.010, P less than 0.01). Concomittently (HCO3-)a decreases in ANTU-treated rats (22.2 +/- 1.2 mmol l-1 vs 24.8 +/- 0.6 mmol l-1, P less than 0.01). The absence of hypoxaemia is common with normobaric oxygen (02) and ANTU-induced lung oedema in the rat. A comparison is made between 02 and ANTU toxicity, as for respiratory events and histological features.

Topics: Animals; Blood Pressure; Body Temperature; Carbon Dioxide; Heart Rate; Hematocrit; Hydrogen-Ion Concentration; Lactates; Lung; Male; Oxygen; Pulmonary Edema; Rats; Rats, Inbred Strains; Thiourea

In pulmonary edema, fluid accumulates first in the interstitium, then in the alveoli. However, the relative amounts of interstitial fluid around arteries and veins of different sizes are unknown; in addition, the effects of fixation on the light microscopic quantitation of edema are unclear. To answer these questions, we induced permeability pulmonary edema in seven anesthetized dogs with 27 mg/kg of alpha-naphthylthiourea. Pulmonary artery and wedge pressures were measured. After moderately severe edema, diagnosed by chest x-ray and falling arterial pO2, lobes were fixed by airways instillation or vascular perfusion with glutaraldehyde and formaldehyde or were frozen with liquid nitrogen. With light microscopy, the edema surrounding arteries and veins of different sizes was measured using a computer equipped with a digitizing tablet and expressed as the edema ratio = area of perivascular edema/area of vessel, or as an absolute area of edema. Alveolar edema was graded semiquantitatively, and wet weight to dry weight ratios were calculated. Two control dogs were also studied. During the induction of edema, pulmonary artery and wedge pressures did not change significantly. Mean wet weight to dry weight ratios were 9.3 +/- 1.1. We found that the edema ratio was greater (p less than 0.01) for arteries (2.75, n = 1305) than for veins (1.40, n = 900). The edema ratio was greater for vessels more than 400 micron than less than 400 micron (p less than 0.01) and greater in the instillation- and perfusion-fixed lobes than in the frozen lobes (p less than 0.01). Similar results were obtained for the absolute areas of periarterial and perivenous edema. Less alveolar edema was seen in the lobes fixed by instillation (p less than 0.01). We conclude that, in permeability edema induced by alpha-naphthylthiourea, the fluid accumulates preferentially around arteries compared with veins and around larger compared with smaller vessels. Airways instillation and vascular perfusion fixation appeared to increase interstitial fluid cuffs compared to freezing.

Topics: Animals; Capillary Permeability; Dogs; Female; Male; Pulmonary Alveoli; Pulmonary Artery; Pulmonary Edema; Pulmonary Veins; Thiourea

Thiourea (TU), a very effective hydroxyl radical (.OH) scavenger, has little value as a probe of .OH in vivo because it causes fatal pulmonary edema. To test the hypothesis that TU-induced lung injury results from .OH-mediated oxidation of TU to toxic cyanamide, we pretreated rats with .OH scavengers, dimethylsulfoxide (DMSO), ethanol, and mannitol, prior to treatment with TU (3 mg/kg), preventing 91, 63, and 53%, respectively, of increases in lung weight to body weight ratios and 93, 67, and 46% of increases in lung lavage albumin concentrations. Furthermore, treatment of rats with cyanamide (CYN) (100 mg/kg) also caused increases in lung weight to body weight ratios (CYN: 7.39 +/- 0.57 X 10(-3) vs. controls: 5.46 +/- 0.26). N,N'-dimethylation of TU (DMTU) prevented TU toxicity, because treatment with DMTU did not significantly increase lung weight to body weight ratios (DMTU: 5.12 +/- 0.16 X 10(-3) vs. controls: 5.46 +/- 0.26) or lung lavage albumin (DMTU: 14 +/- 1 mg/100 ml vs. controls: 11 +/- 1). DMTU remained a very effective in vivo .OH scavenger, increasing survival of lethally irradiated mice treated with 600 mg/kg DMTU to 79% compared with 8% in untreated controls.

Topics: Animals; Cyanamide; Dimethyl Sulfoxide; Ethanol; Lung; Mannitol; Methane; Pulmonary Edema; Radiation Injuries, Experimental; Rats; Rats, Inbred Strains; Thiourea

Topics: Angiotensin II; Animals; Capillary Permeability; Lung; Male; Oxygen; Pulmonary Edema; Rats; Rats, Inbred Strains; Thiourea; Vasoconstriction

The effect of pulmonary oedema on the pharmacokinetic function of rat lungs was studied using prostaglandin E2 (PGE2) as substrate; oedema was induced by alpha-naphthyl thiourea (ANTU). Male rats were given a single i.p. injection of ANTU (10 mg/kg). Lung wet weight, dry:wet weight ratio and pleural transudate were measured at fixed times up to 50 hr after treatment. Wet weight was increased after 4 hr and remained higher than controls until 50 hr; dry:wet weight ratios were different only at 6 and 16 hr. Survival of PGE2 (measured by bioassay) was increased at 4 hr, reached a peak value of about six times the control survival at 6 hr and returned to normal by 50 hr. Using 14C-PGE2 as substrate, survival was maximal at 16 hr and back to normal by 50 hr. The efflux profiles of radioactivity showed an increase in T1/2 by 4 hr rising to a maximum at 28 hr and a normal value at 50 hr. Changes in PGE2 survival precede the period of oedema (assessed by dry:wet ratio) and could be used as an early warning of oedematous states. This altered pharmacokinetic function of lung could also have systemic effects.

Topics: Animals; Dinoprostone; Disease Models, Animal; Exudates and Transudates; Inactivation, Metabolic; Kinetics; Lung; Male; Organ Size; Prostaglandins E; Pulmonary Edema; Rats; Rats, Inbred Strains; Thiourea

Topics: Animals; Immunoenzyme Techniques; Male; Microscopy, Electron; Pulmonary Alveoli; Pulmonary Edema; Rats; Thiourea

Pulmonary injury caused by alpha naphthylthiourea (ANTU) is characterized by alterations of the capillary endothelial barrier followed by lung edema. Because pulmonary uptake of 5-hydroxytryptamine (5-HT) is dependent upon active transcellular transport by lung endothelium, it may be an index of early impairment of endothelial function caused by ANTU. We studied the effect of a single intraperitoneal dose of 5 or of 10 mg/kg of ANTU on pulmonary uptake of 5-HT by isolated rat lungs. Four h after the administration of ANTU, when lung tissue structure and dry-to-wet-weight ratios were comparable to those of control animals, 5-HT uptakes were significantly reduced (p < 0.05). Twenty-four h after the administration of ANTU, when lung edema was present on histologic examination and by lung weights, 5-HT uptakes were further reduced. They returned to control values 14 days after the administration of ANTU. Depression of 5-HT uptake is an early and reversible alteration of lung endothelial cell function caused by ANTU. Uptake of 5-HT may provide a sensitive probe with which to detect and evaluate pulmonary endothelial cell injury caused by toxicants.

Topics: Animals; Biological Transport, Active; Capillaries; Endothelium; In Vitro Techniques; Lung; Male; Naphthalenes; Organ Size; Pulmonary Edema; Rats; Serotonin; Thiourea

Administration of endotoxin prior to an LD50 dose of thiourea protected rats against pulmonary edema and pleural effusion. These results are similar to those seen with endotoxin pretreatment and pulmonary O2 toxicity.

Topics: Animals; Endotoxins; Escherichia coli; Male; Pleural Effusion; Pulmonary Edema; Rats; Thiourea; Time Factors

Topics: Animals; Freeze Fracturing; Lung; Male; Microscopy, Electron; Pulmonary Edema; Rats; Thiourea

The administration of an acute pulmonary edemagenic dose (ip) of thiourea to rats results in an elevation of angiotensin converting enzyme (ACE) in serum, lung lavage, and pleural effusion. The increased serum ACE corresponds to a reduction in lung ACE, but it is transient, lasting between 1 and 2 h. ACE remains elevated in lung lavage and pleural effusion for at least 4 h after the administration of thiourea.

Topics: Acute Disease; Animals; Disease Models, Animal; Lung; Male; Peptidyl-Dipeptidase A; Pleural Effusion; Pulmonary Edema; Rats; Therapeutic Irrigation; Thiourea

Small dosages of endotoxin (100--500 micrograms/kg) provide significant protection against the acute manifestations of pulmonary O2 toxicity and lethality. Ninety-seven percent of endotoxin-treated adult rats survived a 72-h exposure to greater than or equal to 95% O2 with mimimal lung changes, compared to 32% of control animals (P less than 0.01). Exposure to greater than or equal to 95% O2 for 7 days resulted in a 20% survival rate in untreated control rats vs. 98% survival in endotoxin-treated rats (P LESS THan 0.01). Histological evaluation of lung from survivors revealed substantially less collagen and reticular fiber deposition in the endotoxin-treated animal lungs. Endotoxin treatment was associated with increased activity of the protectant antioxidant enzyme systems of the lung in an apparent dose-response manner. Endotoxin's protective activity against O2 toxicity does not appear to depend on an initial toxic insult to the lung like with alpha-naphthylthiourea, oleic acid, or alloxan treatment. The data support a protective role for endotoxin against the acute and the more chronic manifestations of O2-induced pulmonary injury.

Topics: Alloxan; Animals; Dose-Response Relationship, Drug; Endotoxins; Hemorrhage; Lung Diseases; Oleic Acids; Oxygen; Pulmonary Edema; Pulmonary Fibrosis; Rats; Thiourea

Clonogenic growth (colony-forming efficiency, CFE) of i.v. injected allogeneic W256 tumour cells in the lungs was markedly enhanced by treatment of rats with alpha-naphthyl thiourea (ANTU) injected i.p. from 2 h before to 2 h after the tumour cells. ANTU specifically increases pulmonary vascular permeability in adult rats and causes acute pulmonary oedema and pleural effusion. Inhibition of drug toxicity to the lungs by tachyphylaxis, specific antimetabolites or iodides did not abolish the effect of ANTU on CFE. CFE was not increased when cells were seeded by i.v. injection the lungs affected by advanced pulmonary oedema at 6 to 24 h after treatment with drug. ANTU did not enhance growth of intratracheally injected cells. Although ANTU has no cytotoxic or immunosuppressive action, treatment of tumour-immunized rats with ANTU caused apparent "breakdown" of tumour immunity in 50% of rats, by causing growth of tumour colonies in the lungs. Possible mechanisms for the ANTU-induced decrease in innate resistance to growth of tumour in the lungs are discussed.

Topics: Adrenalectomy; Animals; Carcinoma 256, Walker; Clone Cells; Dose-Response Relationship, Drug; Female; Injections; Lung Neoplasms; Neoplasm Transplantation; Pleural Effusion; Pulmonary Edema; Rats; Tachyphylaxis; Thiourea; Thyroidectomy; Time Factors

The pulmonary absorption of 14C-labeled urea, mannitol, inulin, and dextran was measured in vivo in anesthetized rats with alpha-naphthylthiourea (ANTU)-induced (5 mg/kg, ip) lung edema. At 1 h after ANTU treatment, the absorption of mannitol was significantly increased; in 4-h ANTU-treated animals, the absorption of urea was unchanged, whereas the absorption of mannitol, inulin and dextran was increased markedly compared to controls. Although disappearance of each solute from control lungs could be described by a single, first-order rate, absorption time curves for mannitol and inulin showed at least two components in edematous lungs: a fast component(s) and a slower, first-order component; fast-component rates for the two saccharides appeared to be similar; the slow-component rate for each compound was not significantly different from its control rate. The results suggest that fast-component absorption in ANTU-treated rats represents a fraction of instilled solute which entered damaged areas of lung where the porosity of the absorbing membranes was markedly increased, whereas slow-component absorption occurred from normal areas of lung.

Topics: Animals; Cell Membrane Permeability; Dextrans; Epithelium; Inulin; Kinetics; Lung; Male; Mannitol; Naphthalenes; Pulmonary Edema; Rats; Thiourea; Urea

The pulmonary absorption and uptake of (35S)phenol red ((35S)PR was measured in anesthetized rats with alpha-naphthylthiourea- (ANTU) induced lung edema. When (35S)PR solution was injected through a tracheal cannula in control animals and the percentage of the tracheal cannula in control animals and the percentage of the dose unabsorbed plotted semilogarithmically against time, an apparent first-order absorption rate was obtained. In contrast, in rats with ANTU-induced edema, the absorption time curve showed at least two different first-order components. Increasing the concentration of (35S)PR from 0.01 to 3 mM resulted in a decrease in the percentage absorption of the compound in controls compared with a relatively constant percentage absorption in edematous lungs. (35S)PR uptake by lung slices from ANTU-treated rats was decreased in the presence of IAA and a N2 atmosphere, and the dye accumulated at a faster rate and to a greater extent than in controls. The results suggest that although energy-dependent drug transport mechanisms remain intact, the porosity of the absorbing membranes and the extent of drug binding in the lung are increased markedly in the presence of edema.

Topics: Animals; Biological Transport; Energy Metabolism; Lung; Male; Permeability; Pharmaceutical Preparations; Phenolsulfonphthalein; Pulmonary Edema; Rats; Thiourea

Topics: Acetylcholinesterase; Animals; Cholinesterase Inhibitors; In Vitro Techniques; Kinetics; Lung; Male; Organ Size; Pulmonary Edema; Rats; Thiourea

A comparative study of the ultrastructural changes in rat pulmonary vessels was made in two different situtations of increased vascular permeability: one caused by alpha-naphthylthiourea (ANTU) and the other induced by ammonium sulphate (AS). AS had a more destructive effect on the capillaries but showed little alteration in vessels larger than capillaries. ANTU provoked milder ultrastructural lesions but acted on capillaries, arterial and venous structures. In both conditions intravenously injected carbon particles adhered to the vessel wall and leakage into the interstitial space was rarely seen despite the presence of endothelial gaps. It was concluded that ANTU and AS provoke different ultrastructural alterations and that pulmonary and systemic vessels react differently when undergoing changes in permeability.

Topics: Ammonium Sulfate; Animals; Capillaries; Capillary Permeability; Pulmonary Artery; Pulmonary Edema; Pulmonary Veins; Rats; Thiourea

During the 3rd and 4th weeks of life rats were highly resistant to the toxic effects of alpha-naphthyl thiourea (ANTU) and of thiourea and its derivatives but toxicity developed rapidly during the following 2 weeks. Marked resistance to lung damage by toxic thioureas could be induced in older, mature rats by pretreatment with the toxic agent itself (tachyphylaxis), with other toxic and non-toxic antithyroid drugs or with iodine or iodide--even if the rats were pretreated at an early age before susceptibility to the agent developed. ANTU-tachyphylaxis was dose-dependent. Total thyroidectomy did not affect either lung damage induced by ANTU or the resistance due to tachyphylaxis or to pretreatment with iodide or the antithyroid drugs thiourea, 1-ethyl-1-phenyl thiourea or propyl thiouracil. Neither total nor medullary adrenalectomy affected ANTU toxicity. Marked resistance to ANTU-induced lung damage was induced in rats by pretreatment with either an activator (3-4 benzypyrene) or an inhibitor (SKF 525-A) of drug-metabolizine mixed-function microsomal enzyme systems; the inhibitor, sodium phenobarbitone, had no significant effect on toxicity. The sulphydryl compound, AET, induced marked resistance to ANTU; cysteine was less effective. Neither autonomic blockade with nicotine and atropine nor actinomycin D had significant effects on toxicity to ANTU. The acute pulmonary oedema induced in rats by high pressure oxygen, chemical convulsants, pressor agents and ammonium sulphate differed in many respects from that induced by toxic thioureas; it was typically haemorrhagic in nature, did not result in significant pleural effusion, did not exhibit tachyphylaxis, and was not influenced by pretreatment with iodide or derivatives of thiourea.

Topics: Age Factors; Animals; Drug Resistance; Female; Lung; Organ Size; Pleural Effusion; Potassium Iodide; Proteins; Pulmonary Edema; Rats; Rats, Inbred Strains; Specific Pathogen-Free Organisms; Tachyphylaxis; Thiourea; Thyroidectomy

The relationship between right duct lymph flow and extravascular lung water was studied in 3 normal dogs and 15 dogs with pulmonary edema induced by alpha-naphthylthiourea (ANTU). Right duct lymph was collected in a pouch created by ligating jugular, subclavian, and brachiocephalic veins. Extravascular lung water was measured in vivo by double indicator dilution and post-mortem by weighting lungs before and after drying. Cardiac output, pulmonary artery and pulmonary artery wedge pressures, and the concentration of protein and electrolytes in plasma and right duct lymph were determined. Eight lungs were examined by light and electron microscopy. There was a direct relationship between right duct lymph flow (RDLF in milliters per hour per gram dry lung) and extravascular lung water (Qwl in milliliters per gram dry lung) which was best described by the equation RDLF=0.75-0.26 Qwl+0.03 (Qwl).2 Dogs with severe ANTU-induced edema had extensive lung capillary endothelial destruction but only mild interstitial swelling and no visible damage to type I alveolar epithelial cells. Cardiac output, pulmonary artery and wedge pressures, and protein and electrolyte concentrations did not correlate with either extravascular water or right duct flow. Thus, in ANTU-induced pulmonary edema right duct lymph flow was directly related to extravascular lung water with the highest flows occurring with severe edema. The absence of a rapid increase in lymph flow with small increases in extravascular water may be due to early sequestration of fluid in the alveolar space. Hemodynamic changes did not account for changes in lung water or lymph flow. The pulmonary interstitial factors relating increased extravascular water to lymph drainage remain to be determined.

Topics: Animals; Blood Pressure; Blood Proteins; Body Water; Cardiac Output; Dogs; Electrolytes; Lung; Lymph; Lymphatic System; Pleural Effusion; Pulmonary Artery; Pulmonary Edema; Thiourea; Vascular Resistance

Intratracheal (i.t.) administration of protein synthesis inhibitors produced pulmonary edema. Of those inhibitors studied, dactinomycin (act. D) was the most potent. Severity of lung damage due to act. D was dose- and almost age-related. Maximal intensity of pulmonary edema was reached on the 3rd day following administration and remained constant for 14 days. Histopathological studies revealed confluent edema of the entire lung. Pretreatment with act D induced tolerance to an LD100 edematogenic dose of thiourea. The effects of i.t. instillation of act. D appear to be localized in the pulmonary tissue. Lung lavage fluid collected from drug-treated rats had higher acid and alkaline phosphatase activities, higher protein content and more leukocyte infiltration than that of control.

Topics: Animals; Dactinomycin; Drug Tolerance; Intubation, Intratracheal; Liver; Lung; Male; Phosphoric Monoester Hydrolases; Protein Biosynthesis; Pulmonary Edema; Rats; Thiourea; Time Factors

Topics: Aging; Animals; Capillary Permeability; Male; Pulmonary Edema; Rats; Thiourea

Topics: Adenosine Triphosphatases; Animals; DNA; Histamine; Lung; Male; Organ Size; Ozone; Phenylthiourea; Pulmonary Edema; Rats; Thiourea

Topics: Animals; Body Weight; Capillary Permeability; Dactinomycin; Dose-Response Relationship, Drug; Drug Synergism; Intubation, Intratracheal; Lung; Male; Organ Size; Peritoneal Diseases; Pleural Effusion; Pulmonary Edema; Rats; Thiourea; Time Factors

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Hematocrit; Hypoproteinemia; Lung; Male; Naphthalenes; Pleural Effusion; Pulmonary Alveoli; Pulmonary Edema; Pulmonary Fibrosis; Rats; Recurrence; Rodenticides; Tachyphylaxis; Thiourea

Topics: Animals; Aorta, Abdominal; Bacterial Infections; Constriction; Hypoxia; Lung; Macrophages; Male; Mice; Phagocytosis; Phosphorus Radioisotopes; Pneumonia; Pulmonary Alveoli; Pulmonary Edema; Rats; Staphylococcal Infections; Thiourea

Topics: Aconitum; Ammonium Chloride; Animals; Epinephrine; Microscopy, Fluorescence; Pulmonary Edema; Pulmonary Surfactants; Rats; Thiourea

Topics: Animals; Cell Count; Disease Models, Animal; Epithelium; Hypoxia; Injections, Intraperitoneal; Lung; Macrophages; Male; Microscopy, Electron; Naphthalenes; Oxygen; Pulmonary Alveoli; Pulmonary Edema; Rats; Respiration; Thiourea

Topics: Animals; Epinephrine; Fibrin; Male; Naphthalenes; Pulmonary Alveoli; Pulmonary Edema; Rats; Rodenticides; Thiourea

Topics: Animals; Asphyxia; Drowning; Electron Transport Complex IV; Fructose-Bisphosphate Aldolase; Lung; Male; Myocardium; Organ Size; Peroxidases; Pulmonary Edema; Rats; Statistics as Topic; Thiourea

Topics: Animals; Dactinomycin; Drug Tolerance; Ethionine; Male; Phenylthiourea; Pleural Effusion; Pulmonary Edema; Rats; Thiourea

Topics: Animals; Epinephrine; Microscopy, Electron; Pulmonary Alveoli; Pulmonary Edema; Rats; Rodenticides; Thiourea

Topics: Animals; Animals, Newborn; Body Weight; Injections, Intraperitoneal; Mice; Nitrogen Dioxide; Organ Size; Pulmonary Edema; Rats; Thiourea

Topics: Animals; Lung; Lymphatic System; Pulmonary Edema; Rabbits; Rats; Thiourea

Topics: Animals; Epinephrine; Pulmonary Edema; Rats; Thiourea

Topics: Animals; Blood Vessels; Carbon; Epinephrine; Fibrin; Pulmonary Edema; Quaternary Ammonium Compounds; Rats; Thiourea

Topics: Communication; Edema; Pneumonia; Pulmonary Edema; Thiourea

Topics: Cardiovascular Diseases; Pneumonia; Pulmonary Edema; Thiourea

Topics: Edema; Hemodynamics; Lung Diseases; Pulmonary Edema; Thiourea

Topics: Edema; Pulmonary Edema; Thiourea

Topics: Animals; Dogs; Edema; Lung Diseases; Oxygen; Pulmonary Edema; Respiration; Thiourea

Topics: Animals; Exudates and Transudates; Lung Diseases; Pleura; Pleural Effusion; Pulmonary Edema; Rats; Thiourea

Topics: Alkaloids; Edema; Epinephrine; Pulmonary Edema; Salicylates; Thiourea

Topics: Animals; Anura; Dogs; Lung; Mice; Pulmonary Alveoli; Pulmonary Edema; Rats; Thiourea

Topics: Animals; Dogs; Edema; Lung; Pleural Effusion; Pleurisy; Pulmonary Edema; Rats; Thiourea