Inhibition of Matrix Metalloproteinase-9 with Doxycycline Reduces Pancreatitis-Associated Lung Injury

Sochor, M.; Richter, Sabine; Schmidt, Anja; Hempel, Silke; Hopt, Ulrich T.; Keck, Tobias

doi:10.1159/000212080

Cited by 45 publications

(38 citation statements)

References 48 publications

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“…In a separate in vitro experiment, transmigration of neutrophils across matrigel and MMP-9 levels in chamber supernatants were reduced by addition of doxycycline in a concentration to match that achieved in the plasma after subcutaneous administration in the animal experiment [42].…”

Section: Tetracyclinesmentioning

confidence: 95%

“…Subcutaneous administration of doxycycline in a pancreatitis model of lung injury reduces the histological grade of ALI and amount of MMP-9 in lung as detected by an enzyme activity fluorescence assay [42]. In a separate in vitro experiment, transmigration of neutrophils across matrigel and MMP-9 levels in chamber supernatants were reduced by addition of doxycycline in a concentration to match that achieved in the plasma after subcutaneous administration in the animal experiment [42].…”

Section: Tetracyclinesmentioning

confidence: 99%

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Matrix metalloproteinases in acute lung injury: mediators of injury and drivers of repair

Davey¹,

McAuley

O'Kane

2011

European Respiratory Journal

201

156

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Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) comprise a spectrum of acute inflammatory pulmonary oedema resulting in refractory hypoxaemia in the absence of an underlying cardiogenic cause. There are multiple pulmonary and extrapulmonary causes and ALI/ARDS patients are a clinically heterogeneous group with associated high morbidity and mortality.Inflammatory injury to the alveolar epithelial and endothelial capillary membrane is a central event in the pathogenesis of ALI/ARDS, and involves degradation of the basement membrane. Matrix metalloproteinases (MMPs) have been implicated in a wide variety of pulmonary pathologies and are capable of degrading all components of the extracellular matrix including the basement membrane and key non-matrix mediators of lung injury such as chemokines and cell surface receptors.While many studies implicate MMPs in the injurious process, there are significant gaps in our knowledge of the role of specific proteases at different phases of injury and repair. This article examines the role of MMPs in injury and repair of the alveolar epithelial-endothelial capillary barrier and discusses the potential for MMP modulation in the prevention and treatment of ALI. The need for further mechanistic and in vivo studies to inform appropriate subsequent clinical trials of MMP modulation will be highlighted. KEYWORDS: Acute lung injury, acute respiratory distress syndrome, extracellular matrix, inflammation, matrix metalloproteinases, repair A cute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are part of a disease spectrum associated with high mortality and considerable morbidity. The most recent diagnostic criteria for ALI/ARDS, developed by the 1994 American-European Consensus Conference Committee [1], are based on the gross clinico-radiological findings; acute onset, bilateral infiltrates on chest radiography, absence of left ventricular failure and the ratio of arterial oxygen tension (Pa,O 2 , expressed in mmHg) to inspired oxygen fraction (FI,O 2 ) measuring ,200 (ARDS) or ,300 (ALI) [2][3][4]. However, ALI/ARDS patients are clinically heterogeneous and this definition does not take into account the underlying aetiology or severity of illness reflected by failure of other organ systems [2]. Irrespective of aetiology, the pathogenesis of ALI/ARDS consists of an excessive and inappropriate inflammatory response to a range of pulmonary or extrapulmonary insults, resulting in damage to the alveolar epithelial-endothelial capillary barrier [3,4]. Clinically, this manifests as refractory hypoxaemia and decreased pulmonary compliance. Pathologically, three phases are recognised: an initial acute inflammatory or exudative phase characterised by

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Section: Tetracyclinesmentioning

confidence: 95%

Section: Tetracyclinesmentioning

confidence: 99%

Matrix metalloproteinases in acute lung injury: mediators of injury and drivers of repair

Davey¹,

McAuley

O'Kane

2011

European Respiratory Journal

201

156

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show abstract

“…In contrast, more recent data indicate that MMP9 might have an unrecognised beneficial role in reducing pulmonary oedema in ARDS by improving alveolar epithelial healing [165]. Inhibition of MMP9 activity with doxycycline reduced pancreatitis-associated lung injury and diminished expression of MMP9 in pulmonary tissue [69]. BAL from MMP9-deficient mice exposed to ozone had increased protein content and greater numbers of neutrophils and epithelial cells compared to wild-type mice; this finding points to a protective role of MMP9 in ozone-induced inflammation [35].…”

Section: Acute Lung Injurymentioning

confidence: 99%

A therapeutic role for matrix metalloproteinase inhibitors in lung diseases?

Vandenbroucke¹,

Dejonckheere²,

Libert³

2011

European Respiratory Journal

111

105

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Disruption of the balance between matrix metalloproteinases (MMPs) and their endogenous inhibitors is considered a key event in the development of pulmonary diseases such as chronic obstructive pulmonary disease, asthma, interstitial lung diseases and lung cancer. This imbalance often results in elevated net MMP activity, making MMP inhibition an attractive therapeutic strategy. Although promising results have been obtained, the lack of selective MMP inhibitors, together with limited knowledge regarding the exact functions of a particular MMP, hampers clinical application. This review discusses the involvement of different MMPs in lung disorders and future opportunities and limitations of therapeutic MMP inhibition.

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“…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 in the role that anti-edematous molecules may serve in alleviating this phenomenon (4,6–8). …”

Section: Introductionmentioning

confidence: 99%

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

Chen

Shang

et al. 2014

Experimental and Therapeutic Medicine

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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.

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Inhibition of Matrix Metalloproteinase-9 with Doxycycline Reduces Pancreatitis-Associated Lung Injury

Cited by 45 publications

References 48 publications

Matrix metalloproteinases in acute lung injury: mediators of injury and drivers of repair

Matrix metalloproteinases in acute lung injury: mediators of injury and drivers of repair

A therapeutic role for matrix metalloproteinase inhibitors in lung diseases?

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

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