Effects of hypoxia-inducible factor-1α and matrix metalloproteinase-9 on alveolar-capillary barrier disruption and lung edema in rat models of severe acute pancreatitis-associated lung injury

摘要

The aim of this study was to investigate the effects of hypoxia-inducible factor-1α (HIF-1α) and matrix metalloproteinase-9 (MMP-9) on alveolar-capillary barrier disruption and lung edema in rat models of severe acute pancreatitis-associated lung injury (PALI). A total of 40 male Sprague-Dawley rats were randomly divided into a sham surgery group (n=10) and three PALI groups, in which acute pancreatitis was induced by the retrograde infusion of 5% sodium taurocholate (1 ml/kg). The PALI groups were as follows: i) Untreated PALI group (n=10); ii) 2-methoxyestradiol (2ME2) group (5 mg/kg body mass; n=10); and iii) 2ME2 group (15 mg/kg body mass; n=10). In the two 2ME2 groups, the HIF-1α inhibitor 2ME2 was administered intraperitoneally 1 h after the induction of AP. The severity of the pancreatitis was evaluated by the serum amylase levels and pathology. The severity of the lung injury was evaluated by the wet/dry ratio, blood gas analysis and pathology. The alveolar-capillary barrier disruption was assessed by Evans blue dye extravasation. The protein and mRNA expression levels of HIF-1α and MMP-9 were studied using enzyme-linked immunosorbent assays (ELISAs), western blot analysis and reverse transcription-polymerase chain reaction. The active tumor necrosis factor-α levels were measured using an ELISA. The HIF-1α inhibitor 2ME2 attenuated the severity of the pancreatitis and PALI, while the lung edema and alveolar-capillary barrier disruption were significantly ameliorated compared with those in the untreated PALI group. Administration of the higher dose of 2ME2 significantly suppressed the protein expression of MMP-9 in the lung tissues. The results indicate that HIF-1α has a major function in alveolar-capillary barrier disruption and lung edema in PALI via a molecular pathway cascade involving MMP-9. Inhibition of HIF-1α by 2ME2 attenuates alveolar-capillary barrier disruption and lung edema. Pharmacological blockade of this pathway in patients with PALI may provide a novel therapeutic strategy.