OXYGEN-INDUCED LUNG INJURY IN THE PRETERM GUINEA-PIG - THE ROLE OF LEUKOTRIENE B-4

Leukotriene B-4 (LTB(4)) has been reported to promote the formation of lung oedema when infused into the pulmonary circulation of adult animals. The present study evaluated the hypothesis that LTB(4) was responsible, in part, for the oedema that develops during oxidative injury of the immature lung. Significant increases were found in LTB(4) concentration in bronchoalveolar lavage fluid obtained from pre-term guinea pig pups maintained in 95% oxygen for 48 h (P<0.05) and 72 h (P<0.05) compared to pups maintained in 21% oxygen. Cellular analysis of lavage fluid revealed a concurrent influx of neutrophils into the hyperoxic-injured lung at these times. The protein concentration of lavage fluid was also increased by 48-h hyperoxia exposure indicating elevated pulmonary microvascular permeability. In a second series of experiments, pups exposed to 95% oxygen (and 21% oxygen controls) were treated with a specific LTB(4) antagonist (U-75302), at either 0.5, 1.5 or 3.0 mg 100 g body wt to ascertain if LTB(4) played a role in either neutrophil recruitment or oedema formation in the immature lung. The number of neutrophils recovered in bronchoalveolar lavage fluid was significantly reduced, compared to vehicle-treated pups, in pups treated with U-75302, at both 1.5 and 3.0 mg/100 g body wt but not 0.5 mg/100 g body wt. Histopathological analysis of pups treated with 1.5 mg U-75302/100 g body wt revealed fewer neutrophils in the pulmonary interstitium (198 vs. 218 mm(-2), P<0.05). The extent of lung microvascular permeability, elevated by hyperoxic exposure, was modulated by increasing concentrations of U-75302. Specifically, treatment with 0.5, 1.5 and 3.0 mg U-75302/100 g body wt reduced microvascular permeability by 17, 67 and 98%, respectively. In conclusion, LTB(4) plays an important role in oedema formation in acute oxidative injury of the immature lung and this is mediated, in part, through neutrophils.