tetracycline and Pulmonary-Edema

Primary and secondary pneumothoraces are relatively common problems in a busy chest physician's practice. Management options are often different when dealing with primary or secondary pneumothoraces because the underlying cause is different. Thoracoscopy will have a major impact on the surgical approach used in these patients, whereas the advent of lung transplantation has led to a more cautious approach toward the use of sclerosing agents in potential lung transplant recipients.

Topics: Barotrauma; Chest Tubes; Drainage, Postural; Humans; Pleura; Pneumothorax; Positive-Pressure Respiration; Pulmonary Edema; Talc; Tetracycline; Thoracotomy

Topics: Hemopneumothorax; Humans; Mediastinal Emphysema; Pneumothorax; Pulmonary Edema; Sclerosing Solutions; Suction; Tetracycline; Thoracostomy; Thoracotomy

Sepsis causes more than with 215,000 deaths per year in the United States alone. Death can be caused by multiple system organ failure, with the lung, in the form of the acute respiratory distress syndrome (ARDS), often being the first organ to fail. We developed a chronic porcine model of septic shock and ARDS and hypothesized that blocking the proteases neutrophil elastase (NE) and matrix metalloproteinases (MMP-2 and MMP-9) with the modified tetracycline, COL-3, would significantly improve morbidity in this model. Pigs were anesthetized and instrumented for hemodynamic monitoring and were then randomized to one of three groups: control (n = 3), laparotomy only; superior mesenteric artery occlusion (SMA) + fecal blood clot (FC; n = 7), with intraperitoneal placement of a FC; and SMA + FC + COL (n = 5), ingestion of COL-3 12 h before injury. Animals emerged from anesthesia and were monitored and treated with fluids and antibiotics in an animal intensive care unit continuously for 48 h. Serum and bronchoalveolar lavage fluid (BALF) were sampled and bacterial cultures, MMP-2, MMP-9, NE, and multiple cytokine concentrations were measured. Pigs were reanesthetized and placed on a ventilator when significant lung impairment occurred (PaO2/FiO2 < 250). At necropsy, lung water and histology were assessed. All animals in the SMA + FC group developed septic shock evidenced by a significant fall in arterial blood pressure that was not responsive to fluids. Lung injury typical of ARDS (i.e., a fall in lung compliance and PaO2/FiO2 ratio and a significant increase in lung water) developed in this group. Additionally, there was a significant increase in plasma IL-1 and IL-6 and in BALF IL-6, IL-8, IL-10, NE, and protein concentration in the SMA + FC group. COL-3 treatment prevented septic shock and ARDS and significantly decreased cytokine levels in plasma and BALF. COL-3 treatment also significantly reduced NE activity (P < 0.05) and reduced MMP-2 and MMP-9 activity in BALF by 64% and 34%, respectively, compared with the SMA + FC group. We conclude that prophylactic COL-3 prevented the development of ARDS and unexpectedly also prevented septic shock in a chronic insidious onset animal model of sepsis-induced ARDS. The mechanism of this protection is unclear, as COL-3 inhibited numerous inflammatory mediators. Nevertheless, COL-3 significantly reduced the morbidity in a clinically applicable animal model, demonstrating the possibility that COL-3 may be useful in reduc

Topics: Animals; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Female; Inflammation; Interleukin-1; Interleukin-10; Interleukin-6; Interleukin-8; Leukocyte Elastase; Lung; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mesenteric Artery, Superior; Models, Chemical; Oxygen; Peptide Hydrolases; Pulmonary Edema; Respiratory Distress Syndrome; Sepsis; Swine; Tetracycline; Tetracyclines; Time Factors

The acute respiratory distress syndrome (ARDS) occurs in patients with clearly identifiable risk factors, and its treatment remains merely supportive. We postulated that patients at risk for ARDS can be protected against lung injury by a prophylactic treatment strategy that targets neutrophil-derived proteases. We hypothesized that a chemically modified tetracycline 3 (COL-3), a potent inhibitor of neutrophil matrix metalloproteinases (MMPs) and neutrophil elastase (NE) with minimal toxicity, would prevent ARDS in our porcine endotoxin-induced ARDS model.. Yorkshire pigs were anesthetized, intubated, surgically instrumented for hemodynamic monitoring, and randomized into three groups: (1) control (n = 4), surgical instrumentation only; (2) lipopolysaccharide (LPS) (n = 4), infusion of Escherichia coli lipopolysaccharide at 100 microg/kg; and (3) COL-3 + LPS (n = 5), ingestion of COL-3 (100 mg/kg) 12 h before LPS infusion. All animals were monitored for 6 h following LPS or sham LPS infusion. Serial bronchoalveolar lavage (BAL) samples were analyzed for MMP concentration by gelatin zymography. Lung tissue was fixed for morphometric assessment at necropsy.. LPS infusion was marked by significant (P < 0.05) physiological deterioration as compared with the control group, including increased plateau airway pressure (P(plat)) (control = 15.7 +/- 0.4 mm Hg, LPS = 23.0 +/- 1.5 mm Hg) and a decrement in arterial oxygen partial pressure (P(a)O(2)) (LPS = 66 +/- 15 mm Hg, Control = 263 +/- 25 mm Hg) 6 h following LPS or sham LPS infusion, respectively. Pretreatment with COL-3 reduced the above pathophysiological changes 6 h following LPS infusion (P(plat) = 18.5 +/- 1.7 mm Hg, P(a)O(2) = 199 +/- 35 mm Hg; P = NS vs control). MMP-9 and MMP-2 concentration in BAL fluid was significantly increased between 2 and 4 h post-LPS infusion; COL-3 reduced the increase in MMP-9 and MMP-2 concentration at all time periods. Morphometrically LPS caused a significant sequestration of neutrophils and monocytes into pulmonary tissue. Pretreatment with COL-3 ameliorated this response. The wet/dry lung weight ratio was significantly greater (P < 0.05) in the LPS group (10.1 +/- 1.0 ratio) than in either the control (6.4 +/- 0.5 ratio) or LPS+COL-3 (7.4 +/- 0.6 ratio) group.. A single prophylactic treatment with COL-3 prevented lung injury in our model of endotoxin-induced ARDS. The proposed mechanism of COL-3 is a synergistic inhibition of the terminal neutrophil effectors MMPs and NE. Similar to the universal practice of prophylaxis against gastric stress ulceration and deep venous thromboses in trauma patients, chemically modified tetracyclines may likewise be administered to prevent acute lung injury in critically injured patients at risk of developing ARDS.

Topics: Animals; Antibiotics, Antineoplastic; Bronchoalveolar Lavage Fluid; Cardiac Output; Gelatin; Lipopolysaccharides; Metalloendopeptidases; Neutrophils; Pancreatic Elastase; Pulmonary Alveoli; Pulmonary Edema; Respiratory Distress Syndrome; Swine; Tetracycline; Tetracyclines

Lung clearance of Diplococcus pneumoniae was markedly reduced in rats with acute hemorrhagic pulmonary edema produced by instillation of hydrochloric acid. Bacterial clearance was enhanced in both control and acid-instilled animals by pretreatment with a bacteriostatic antibiotic, tetracycline, 30 mg/kg. From these data the contributions of bacterial multiplication and bacterial elimination to net lung bacterial clearance were estimated. In control animals the constant for exponential bacterial elimination was -1.4283 (fractional clearance = 76% per h), and the doubling time for the pneumococcus was 170 min. In acid-instilled rats the elimination constant was -0.5336 (fractional clearance = 41% per h), and the doubling time of the pneumococcus was 47 min, approximating the doubling time of 42 min observed with pneumococci grown in broth. These results indicate that, in the case of pneumococci, both bacterial elimination and bacterial growth contribute to lung bacterial clearance in normal animals as well as animals with damaged lungs. In the present study changes in both parameters were required to explain the observed results in acid-instilled animals. The pulmonary pathogenicity of some bacterial species may be determined by their capacity for growth in the lung, since infection of the lung occurs when bacterial multiplication exceeds the rate of elimination of viable organisms.

Topics: Aerosols; Animals; Hydrochloric Acid; Lung; Male; Pulmonary Edema; Rats; Streptococcus pneumoniae; Tetracycline

Topics: Acute Disease; Aged; Furosemide; Heart Failure; Humans; Lanatosides; Male; Morphine; Oxygen Inhalation Therapy; Pulmonary Edema; Reserpine; Tetracycline

Topics: Acidosis; Adult; Female; Humans; Lactates; Phenformin; Pulmonary Edema; Pyelonephritis; Tetracycline