Oxygen-induced lung injury in the pre-term guinea pig: the role of leukotriene B 4

Abstract

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.