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

Bing Qi,Hai-Long Chen,Gui-Xin Zhang,Lei Yu,Ying Dong,Dong Shang

doi:10.3892/etm.2014.1810

Abstract

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.

Highlights

Acute pancreatitis (AP) is an inflammatory disorder in which a complex cascade of immunological events develops, which affects the pathogenesis and clinical course of the disease, varying from a mild, self‐limiting, transient illness to a severe, fatal outcome [1]
The results indicate that hypoxia‐inducible factor‐1α (HIF‐1α) has a major function in alveolar‐capillary barrier disruption and lung edema in pancreatitis‐associated lung injury (PALI) via a molecular pathway cascade involving Matrix metalloproteinases (MMPs)‐9
Previous studies have demonstrated that HIF‐1α may regulate Matrix metalloproteinase‐9 (MMP‐9) expression in the pathogenesis of blood‐brain barrier disruption and brain edema following brain injury [4,22]

Summary

Introduction

Acute pancreatitis (AP) is an inflammatory disorder in which a complex cascade of immunological events develops, which affects the pathogenesis and clinical course of the disease, varying from a mild, self‐limiting, transient illness to a severe, fatal outcome [1]. Previous studies have demonstrated that pulmonary edema following PALI causes pulmonary swelling, which produces secondary microvascular leakage, alveolar‐capillary barrier disruption, and even alveolar damage and mortality [3,4,5]. In severe PALI, pulmonary edema poses a critical clinical problem due to its association with acute respiratory function failure [6]. Despite the fact that there have been significant advances in the understanding of the pathogenesis of alveolar‐capillary barrier disruption and lung edema of PALI, as well as the availability of existing PALI treatments that attenuate the aforementioned derangements, the molecular mechanisms underlying this phenomenon remain poorly understood. The lack of effective drugs to ameliorate the initiation and progression of PALI‐induced alveolar‐capillary barrier disruption and lung edema has led to increased interest

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