thiourea and Streptococcal-Infections

To elucidate the possible roles of nitric oxide (NO), endothelin-1 (ET-1), and reactive oxygen species (ROS) in the pathophysiology of serogroup A streptococcal (GAS) peritoneal sepsis, we investigated the effects of aminoethylisothiourea (AE-ITU), an inducible NO synthase (iNOS) inhibitor, and a ROS scavenger, and the ET-1 receptor antagonist bosentan. In rats, live GAS inocula, 3 x 10(8) and 1 x 10(9) cfu/kg, entailed a 24-h mortality of 10% and 90%, respectively. GAS caused increases in tissue iNOS activity (9 h), in serum nitrite/nitrate (9-24 h), and in intracellular leukocyte ROS levels (3-6 h). These changes were all prevented by the pre-treatment with AE-ITU. A novel finding was that AE-ITU also prevented the GAS-induced marked increase in plasma ET-1 at 6 h. Short-term (7-h) survival was improved by both AE-ITU and by bosentan. The mechanism(s) for the beneficial effects of AE-ITU may possibly be a combined mode of action; iNOS inhibition, ROS scavenging, and inhibition of the increase in plasma ET-1 caused by GAS.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Bosentan; Endothelin Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Shock, Septic; Streptococcal Infections; Streptococcus pyogenes; Sulfonamides; Survival Rate; Thiourea; Time Factors

To test the effect of a continuous infusion of the nitric oxide (NO) synthase (S) inhibitor aminoethyl-isothiourea (AE-ITU) on survival time, hemodynamics, and oxygen transport in a porcine model of live group A streptococcal (GAS) sepsis. Furthermore, to examine the role of endothelin-1, histamine, and reactive oxygen species (ROS) in streptococcal shock.. Prospective, randomized trial.. Laboratory at a university hospital.. Twenty-eight pigs with an average weight of 25 kg.. Sixteen animals received a continuous infusion of live Streptococcus pyogenes 1.3 x 10(10) colony forming units/hr: eight received fluids only, and the other eight received an intravenous infusion of AE-ITU 10 mg/kg/hr starting 30 mins before the GAS challenge. Six control pigs received AE-ITU 10 mg/kg/hr iv for 5 hrs. Another six animals received half the dose of GAS over 5 hrs.. GAS infusion caused a rapid increase in pulmonary, hepatic, and systemic vascular resistance, followed by hypotension with a 90% lethality at 4 hrs. Treatment with AE-ITU increased 4-hr survival in septic animals from 1/8 to 8/8 and 5-hr survival from 0/8 to 5/8, prevented hypotension, and increased urine output. AE-ITU attenuated the decrease in cardiac output, liver blood flow, and oxygen delivery, and hepatic arterial blood flow as a fraction of cardiac output increased (all p < .05). Plasma nitrate/nitrite levels decreased in all animals. Inducible NOS and endothelial constitutive NOS activities in liver, gut, and lung were not increased during sepsis, nor were they decreased after AE-ITU. Plasma levels of endothelin-1 and methylhistamine increased in all septic animals and were not modified by AE-ITU. AE-ITU prevented the increase in monocyte ROS production caused by GAS. In control animals, AE-ITU caused an increase in mean arterial pressure, liver blood flow, and oxygen delivery.. In this model of porcine GAS-induced septic shock, which was not associated with enhanced NO production, infusion of the NOS inhibitor AE-ITU prolonged survival, prevented hypotension, and improved cardiac contractility, organ perfusion, and tissue oxygenation. These beneficial effects of AE-ITU might be a result of the combined effect of ROS scavenging and modulation of local NO production, thus improving the balance of vasodilator and vasoconstrictor forces and reducing oxidative stress.

Topics: Animals; Disease Models, Animal; Female; Hemodynamics; Isothiuronium; Male; Nitric Oxide; Random Allocation; Shock, Septic; Streptococcal Infections; Streptococcus pyogenes; Survival Rate; Swine; Thiourea

The lung appears to be one of the dominant sites of bacterial clearance from the blood of infant piglets. Part of the lung bacterial clearance involves activation of an oxygen radical bactericidal mechanism that may be central to induction of acute pulmonary hypertension. The present study determined whether this bactericidal activity was intrinsic to resident lung cells. Isolated piglet lung preparations perfused with blood-free salt solution were used to delineate the amount of group B streptococci (GBS) extracted and killed upon transit through pulmonary vasculature. Approximately 45% of infused GBS was deposited in the lung during a single pulmonary transit, whereas nearly 40% of the organisms sequestered in the lung were killed within a 30-min period. Pretreatment with dimethylthiourea, a scavenger of hydroxyl radical that inhibits GBS-induced pulmonary hypertension, attenuated both bacterial uptake and killing to similar extents. Along with its deposition in the lung, GBS also induced concentration-dependent increases in total pulmonary resistance, which were related principally to increases in upstream arterial resistance. Lung weight also increased in a concentration-dependent manner. Both the increase in total pulmonary resistance and lung weight were temporally related to elevation in perfusion medium content of the stable thromboxane degradation product, thromboxane B2. Pretreatment with indomethacin, a prostaglandin H synthase inhibitor, or sodium(E)-3[4-(1-imidazolyl-methyl)phenyl]-2-propenoic acid a thromboxane synthase inhibitor, reduced GBS-induced pulmonary hypertension and edema. These results suggest that, in isolated piglet lungs, GBS evokes an intrinsic bactericidal response residing within lung cells, probably pulmonary intravascular macrophages, which may be responsible for the initiation of pulmonary hemodynamic changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Animals, Newborn; Blood Bactericidal Activity; Hypertension, Pulmonary; In Vitro Techniques; Lung; Pulmonary Circulation; Reactive Oxygen Species; Streptococcal Infections; Streptococcus agalactiae; Swine; Thiourea; Thromboxane B2; Vascular Resistance

The mechanism by which bacteria are cleared by the pulmonary circulation and the relation of this process to development of hemodynamic abnormalities are not understood. This study tested the hypotheses that clearance of Group B Streptococcus (GBS) during transit through the pulmonary circulation of infant piglets is related to oxygen radical-dependent bacterial killing and that killing of the organism is linked to development of pulmonary hypertension. GBS were radiolabeled with 111In and infused intravenously for 15 min (10(8) organisms/kg/min) into infant piglets ranging in age from 5 to 14 days. Lung specimens were excised at termination of the GBS infusion or 45 min thereafter, and both the relative deposition and viability of the bacteria were determined. The percentage of infused GBS recovered in lung tissue did not differ between the two time points (26 +/- 7% versus 29 +/- 8%), but the relative viability at termination of the infusion, 50 +/- 11%, was reduced to 19 +/- 4% within 45 min. Treatment with an oxygen radical scavenger, dimethylthiourea (DMTU), failed to influence the pulmonary deposition of GBS but significantly increased viability of the organism from 21.4 +/- 2.6 to 33.3 +/- 5.3%. As expected, GBS infusion was accompanied by pulmonary hypertension and arterial hypoxemia; DMTU attenuated these responses by 52 and 78%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Disease Models, Animal; Free Radicals; Hemodynamics; Hypertension, Pulmonary; Lung; Oxygen; Pulmonary Circulation; Streptococcal Infections; Streptococcus agalactiae; Swine; Thiourea

Both thromboxane A2 and oxygen-derived free radicals appear to play central roles in group B streptococcus (GBS)-induced pulmonary hypertension in piglets. This study tested the hypothesis that GBS promotes oxygen radical-dependent thromboxane accumulation and pulmonary hypertension in infant piglets. Piglets 4-12 d old were anesthetized and prepared for assessment of pulmonary arterial pressure and arterial blood gases. In control animals, GBS (10(8) organisms/kg/min for 15 min) increased mean pulmonary artery pressure by 30 +/- 1.5 torr and reduced arterial PO2 by 100 +/- 20 torr. Thromboxane A2, radioimmunoassayed in venous blood as thromboxane B2, increased by 2452 +/- 800 pg/mL. A second group of piglets was treated with dimethylthiourea (DMTU: 750 mg/kg), a putative oxygen radical scavenger. In these animals, GBS increased pulmonary arterial pressure by only 7 +/- 1 torr and reduced arterial PO2 by a modest 10 +/- 8 torr. Importantly, thromboxane B2 content in venous blood failed to increase above control levels in DMTU-treated animals. The protective effects of DMTU in GBS-treated piglets could not be ascribed to inhibition of cyclooxygenase or thromboxane synthase because the oxygen radical scavenger failed to attenuate increases in pulmonary arterial pressure and venous thromboxane B2 content or reductions in arterial PO2 caused by i.v. infusions of arachidonic acid. DMTU also did not ameliorate pulmonary hypertension evoked by the thromboxane mimetic U44069, thereby suggesting that the scavenger did not act as an end-organ antagonist of thromboxane receptors. These observations suggest that GBS promotes accumulation of thromboxane A2 and attendant pulmonary hypertension through an oxygen radical-dependent mechanism.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Free Radicals; Hypertension, Pulmonary; Oxygen; Streptococcal Infections; Streptococcus agalactiae; Swine; Thiourea; Thromboxane B2

Dimethylthiourea (DMTU), a putative hydroxyl radical scavenger, attenuates thromboxane generation and pulmonary hypertension in the piglet model of group B streptococcal (GBS) sepsis. This study tested the hypothesis that DMTU reverses ongoing GBS-induced pulmonary hypertension coincident with decreased thromboxane production. Piglets (n = 15) received a 60 min infusion of GBS (10(-8) cfu/kg/min). Mean pulmonary artery pressure (Ppa), arterial blood gases (ABGs), and thromboxane B2 (TXB) levels were measured at 10 min intervals throughout the study. GBS infusion resulted in a marked increase in pulmonary artery pressure (mean delta Ppa = 31 mm Hg) and a significant decline in PaO2 (mean = -80 torr) within 10 min of beginning the infusion. pH decreased from a mean of 7.47 to 7.37. DMTU, 750 mg/kg, or normal saline vehicle was infused over 10-15 min beginning 10 min after initiating GBS. Ppa decreased significantly within 10 min of DMTU infusion. Piglets receiving vehicle had a slow decline in Ppa. Piglets receiving DMTU also had an improvement in PaO2 and showed no further drop in pH. Piglets receiving vehicle had no improvement in PaO2 and demonstrated a continued decline in pH. TXB levels did not differ between the groups at any time interval. We conclude that DMTU can partially reverse GBS-induced pulmonary hypertension, but may function through mechanisms independent of thromboxane generation.

Topics: Animals; Animals, Newborn; Blood Pressure; Disease Models, Animal; Hypertension, Pulmonary; Oxygen; Partial Pressure; Pulmonary Circulation; Sepsis; Streptococcal Infections; Swine; Thiourea; Thromboxane B2

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

Topics: Humans; Staphylococcal Infections; Streptococcal Infections; Sulfanilamide; Sulfanilamides; Sulfonamides; Thiourea