Phosgene, a highly reactive former warfare gas, is a deep lung irritant which produces adult respiratory distress syndrome (ARDS)‐like symptoms following inhalation. Death caused by phosgene involves a latent, 6–24‐h, fulminating non‐cardiogenic pulmonary edema. The following dose‐ranging study was designed to determine the efficacy of a non‐steroidal anti‐inflammatory drug, ibuprofen (IBU), and a methylxanthine, pentoxifylline (PTX). These drugs were tested singly and in combination to treat phosgene‐induced acute lung injury in rats. Ibuprofen, in concentrations of 15–300 mg kg−1 (i.p.), was administered to rats 30 min before and 1 h after the start of whole‐body exposure to phosgene (80 mg m−3 for 20 min). Pentoxifylline, 10–120 mg kg−1 (i.p.), was first administered 15 min prior to phosgene exposure and twice more at 45 and 105 min after the start of exposure. Five hours after phosgene inhalation, rats were euthanized, the lungs were removed and wet weight values were determined gravimetrically. Ibuprofen administered alone significantly decreased lung wet weight to body weight ratios compared with controls (P ⩽ 0.01) whereas PTX, at all doses tested alone, did not. In addition, the decrease in lung wet weight to body weight ratio observed with IBU+PTX could be attributed entirely to the dose of IBU employed. This is the first study to show that pre‐ and post‐treatment with IBU can significantly reduce lung edema in rats exposed to phosgene.
A series of studies was performed to address treatment against the former chemical warfare edemagenic gas phosgene. Both in situ and in vivo models were used to assess the efficacy of postexposure treatment of phosgene-induced lung injury using clinically existing drugs. The degree of efficacy was judged by examining treatment effects on pulmonary edema formation (PEF) as measured by wet/dry weight (WW/DW) ratios, real-time (in situ) lung weight gain (LWG), survival rates (SR), odds ratios, and glutathione (GSH) redox states. Drugs included N-acetylcysteine (NAC), ibuprofen (IBU), aminophylline (AMIN), and isoproterenol (ISO). Using the in situ isolated perfused rabbit lung model (IPRLM), intratracheal (IT) NAC (40 mg/kg bolus) delivered 45-60 min after phosgene exposure (650 mg/m(3)) for10 min lowered pulmonary artery pressure, LWG, leukotrienes (LT) C(4)/D(4)/E(4), lipid peroxidation, and oxidized GSH. We concluded that NAC protected against phosgene-induced lung injury by acting as an antioxidant by maintaining protective levels of GSH, reducing both lipid peroxidation and production of arachidonic acid metabolites. Also in IPRLM, administration of AMIN (30 mg/kg) 80-90 min after phosgene exposure significantly reduced lipid peroxidation and perfusate LTC(4)/D(4)/E(4), reduced LWG, and prevented phosgene-induced decreases in lung tissue cAMP. These data suggest that protective mechanisms observed with AMIN involve decreased LTC(4)/D(4)/E(4) mediated pulmonary capillary permeability and attenuated lipid peroxidation. Direct antipermeability effects of AMIN-induced upregulation of cAMP on cellular contraction may also be important in protection against phosgene-induced lung injury. Posttreatment with ISO in the IPRLM by either combined intravascular (iv; infused into pulmonary artery at 24 microg/min infused) + IT (24 microg bolus) or IT route alone 50-60 min after phosgene exposure significantly lowered pulmonary artery pressure, tracheal pressure, and LWG. ISO treatment significantly enhanced GSH products or maintained protective levels when compared with results from phosgene-exposed only rabbits. These data suggest that protective mechanisms for ISO involve reduction in vascular pressure, decreased LTC(4)/D(4)/E(4)-mediated pulmonary capillary permeability, and favorably maintained lung tissue GSH redox states. For in vivo male mouse (CD-1, 25-30 g) studies IBU was administered ip within 20 min after a lethal dose of phosgene (32 mg/m(3) for 20 min) at 0 (saline), 3, 9, or 15 mg/mouse. Five hours later, a second IBU injection was given but at half the original doses (0, 1.5, 4.5, and 7.5 mg/mouse); therefore, these treatment groups are now referred to as the 0/0, 3/1.5, 9/4.5, and 15/7.5 mg IBU/mouse groups. SRs and odds ratios were calculated for each dose at 12 and 24 h. The 12-h survival was 63% for 9/4.5 mg IBU and 82% for the 15/7.5 mg IBU groups, compared with 25% for saline-treated phosgene-exposed mice. At 24 h, those survival rates were reduced to 19%, 19%, and 6%, respectively. In the 15/7.5 mg IBU...
I Inhalation of toxic doses of phosgene results in varying degrees of pulmonary edema, often after a symptom-free period. The sheep is an anatomically suitable animal in which to study the development of pulmonary edema during that symptom-free period. Five sheep were used in this study, and they were instrumented so as to provide simultaneous information on pulmonary vascular and interstitial fluid dynamics. Through a thoracotomy, the efferent duct of the caudal mediastinal lymph node was .cannulated to monitor pulmonary lymph flow. The sheep were also instrumented with a carotid arterial catheter, a pulmonary artery catheter with thermistor, and a left atrial catheter to monitor systemic and pulmonary hemodynamics. After a 5-to 7-day recovery period, the sheep were given a l0-min nose and mouth exposure to 2.0-2.5 g/m3 of phosgene. Over the next 4 h, there was a two to threefold increase in pulmonary lymph flow, accompanied by a small but significant increase in mean pulmonary microvascular pressure, but no significant change in the ratio of lymph to plasma protein concentration. The pattern of data suggests that aberrant filtration function and, to a much lesser extent, hemodynamic forces contributed to the resulting pulmonary edema. Four hours after exposure the sheep were euthanized and necropsied. Histopathologic examination of lung tissue showed diffuse, moderate alveolar and interlobular edema.
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