Attenuation Of Acute Lung Injury Research Articles

BENEFICIAL EFFECTS OF A THROMBOXANE SYNTHETASE INHIBITOR (UK 38,485) IN RAT ENDOTOXEMIA. 189

The objective of this study was to determine if UK 38,485, a thromboxane synthetase inhibitor (TSI), would prolong survival and attenuate acute lung injury (ALI) in rat endotoxemia. 24 mechanically ventilated rats received 10 mg/kg E. coli LPS. 12 rats received 5 mg/kg TSI, 1 hr prior to LPS infusion. Heart rate, BP, ABG and lactate levels were measured at 0, 30, 60, 90, 120 min. 2 hrs after LPS or at the time of death, alveolar macrophages were collected, washed and resuspended in media. A baseline and 24 hr incubated supernatant were collected for TX, nitric oxide (NO), and PGE2. Rats pretreated with TSI survived longer (117± 3 vs 92± 11 min, p<0.03) and at 30 min had less A-a gradient (247±30 vs 383±44 torr, p<0.01), and acidosis (pH 7.33±.02 vs 7.27±03, p<0.005). No differences in BP, HR, or lactate were observed between the 2 groups. The alveolar macrophages of rats receiving TSI produced more NO at baseline, (fig). Although TX production was inhibited in the plasma of TSI treated endotoxemic rats, the alveolar macrophages continued to produce TX in quantities similar to rats receiving LPS alone,(1000±22 vs 873±223 pg/ml). PGE2 was similar in both groups. Conclusions: TSI prolongs survival in acute endotoxemia by decreasing ALI. The lung protection by TSI appears secondary to an increased production of NO by alveolar macrophages rather than decreased pulmonary TX synthesis.

Attenuation of acute lung injury by ozone inhalation — the effect of low level pre-exposure

The attenuating influence of a pre-exposure of rats to a low concentration of ozone (O 3) for 7 days on a subsequent O 3 challenge was investigated. Effects of O 3 were quantified by measuring indicators of lung permeability and inflammation in bronchoalveolar lavage fluid. The results suggest that pre-exposure to relatively low levels of O 3 produces a diminished permeability response in lower airways of rats upon a following challenge with a higher level of O 3. Extrapolated to human exposure situations, these data suggest that health effect evaluation of repeated exposure periods of enhanced O 3 levels is rather complex and needs further investigation.

Attenuation of acute lung injury and oxygen radical production by the 21-aminosteroid, U-78518F.

Oxygen radicals play an important role in the mechanism of acute lung injury. The 21-aminosteroid lazaroid, U-78518F, is a potent antioxidant. We examined the effect of intravenous U-78518F on acute lung injury in septic guinea pigs over 8 h. The experimental groups (n = 6) were 1) saline control, 2) Escherichia coli (2 x 10(9)/kg i.v.), 3) pretreatment (U-78518F 5 mg/kg bolus + 1 mg.kg-1 x h-1, 15 min before E. coli injection), and 4) posttreatment (U-78518F 30 min after E. coli injection). We measured wet-to-dry weight ratio (W/D) as an index of pulmonary edema and concentration ratios of 125I-labeled albumin in lung tissue and bronchoalveolar lavage fluid compared with plasma (L/P and BAL/P, respectively) as indexes of lung protein fluxes. In septic guinea pigs, pretreatment with U-78518F attenuated W/D, L/P, and BAL/P and posttreatment attenuated W/D and BAL/P (P < 0.05 for each). Furthermore, we studied the effect of U-78518F on human neutrophil oxygen radical production (ORP) by using flow cytometry to assess intracellular ORP and lucigenin-dependent chemiluminescence to assess extracellular ORP. Neutrophils (5 x 10(5) were stimulated with 0.5 micrograms/ml of phorbol myristate acetate. With flow cytometry, we measured intracellular ORP, cross-sectional cell area, and degranulation in neutrophils. U-78518F (minimum concn 1.0 microM) decreased intracellular ORP (n = 4; P < 0.05) when the dihydrorhodamine 123 assay was used. U-78518F (minimum concn 1.0 microM) inhibited phorbol myristate acetate-induced neutrophil chemiluminescence (n = 4; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Attenuation of acute lung injury in septic guinea pigs by pentoxifylline.

Pentoxifylline (PTXF), a drug demonstrated to improve intermittent claudication, is a methylxanthine that increases intracellular cyclic AMP (cAMP) and, unlike theophylline, has few side effects. Because increased cAMP levels have been associated with a decrease in lung injury, we examined the effects of PTXF on acute lung injury in a septic guinea pig model. Five groups of guinea pigs were studied over a period of 8 h. (Group I: saline control injected intravenously with 2 ml of saline; Group II: septic control injected intravenously with 2 x 10(9) Escherichia coli; Group III: E. coli septicemia plus PTXF bolus 20 mg/kg injected 5 min before E. coli injection; Group IV: E. coli septicemia plus PTXF continuous infusion, begun with bolus [20 mg/kg] followed by continuous infusion [20 mg/kg/h] started 60 min before injection of E. coli; Group V: PTXF continuous infusion [20 mg/kg/h] control). Arterial blood gases, arterial blood pressure, and blood WBC counts were monitored serially for 8 h. Lung water (wet-to-dry ratio), the concentration ratio of 125I-labeled albumin in bronchoalveolar lavage (BAL) fluid to that in plasma (albumin index; AI), total cell count in BAL fluid, thiobarbituric-acid-reactive material (TBARM), and the lysosomal enzyme beta-glucuronidase (beta-G) were examined. Lung tissue was studied histologically to assess neutrophil accumulation. Our results showed that E. coli septicemia caused significant peripheral neutropenia and histopathologic evidence of neutrophil alveolitis associated with an increased ratio of TBARM and beta-G in BAL fluid as compared with those in plasma (TBARM BAL ratio and beta-G BAL ratio).(ABSTRACT TRUNCATED AT 250 WORDS)