A rise of MMP-2 and MMP-9 in bronchoalveolar lavage fluid is associated with acute lung injury after cardiopulmonary bypass in a swine model

Eichler, Wolfgang; Bechtel, Matthias; Schumacher, Jan; Wermelt, Johanna A.; Klotz, K.-F.; Bartels, Claus

doi:10.1191/0267659103pf662oa

Cited by 19 publications

(14 citation statements)

References 28 publications

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“…A pig model of lung injury after cardiopulmonary bypass (CPB) also demonstrated a rise of both MMP-2 and -9 in BAL that correlated with the alveolar-arterial oxygen gradient (PA-a,O 2 ) [24]. However, no other markers of lung injury were used in this study to rule out increased PA-a,O 2 caused by a high ventilation/ perfusion ratio or physiological dead space secondary to suboptimal perfusion on CPB.…”

Section: In Vivo Modelsmentioning

confidence: 86%

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

Davey¹,

McAuley

O'Kane

2011

European Respiratory Journal

203

164

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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: In Vivo Modelsmentioning

confidence: 86%

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

Davey¹,

McAuley

O'Kane

2011

European Respiratory Journal

203

164

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“…This has been further supported by demonstration of increases following bleomycin injury in rats [105] and in a pig model of lung injury after cardiopulmonary bypass [106]. In human studies, the results have been more equivocal; one study demonstrated increased levels of MMP-2 and MMP-9, but at lower levels than a matched hospital-acquired pneumonia cohort [107].…”

Section: Pathogenesis Of Ardsmentioning

confidence: 98%

Advances in Understanding of the Pathogenesis of Acute Respiratory Distress Syndrome

2015

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The clinical syndrome of acute lung injury (ALI) occurs as a result of an initial acute systemic inflammatory response. This can be consequent to a plethora of insults, either direct to the lung or indirect. The insult results in increased epithelial permeability, leading to alveolar flooding with a protein-rich oedema fluid. The resulting loss of gas exchange leads to acute respiratory failure and typically catastrophic illness, termed acute respiratory distress syndrome (ARDS), requiring ventilatory and critical care support. There remains a significant disease burden, with some estimates showing 200,000 cases each year in the USA with a mortality approaching 50%. In addition, there is a significant burden of morbidity in survivors. There are currently no disease-modifying therapies available, and the most effective advances in caring for these patients have been in changes to ventilator strategy as a result of the ARDS network studies nearly 15 years ago. Here, we will give an overview of more recent advances in the understanding of the cellular biology of ALI and highlight areas that may prove fertile for future disease-modifying therapies.

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“…Furthermore, increased MMP2 and MMP9 in bronchoalveolar lavage fluid (BALF) have been noted in patients with ARDS (8,28,46). In several experimental models, MMP2 and MMP9 have been implicated in the development of lung injury (7,11,14) while their inhibition attenuated injury (5,14,42,54). Of relevance, a broad-spectrum MMP inhibitor attenuated lung injury caused by high-volume ventilation (14).…”

mentioning

confidence: 99%

Role of MMP2 and MMP9 in TRPV4-induced lung injury

Villalta

Ročić

Townsley

2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Ca(2+) entry through transient receptor potential vanilloid 4 (TRPV4) results in swelling, blebbing, and detachment of the epithelium and capillary endothelium in the intact lung. Subsequently, increased permeability of the septal barrier and alveolar flooding ensue. In this study, we tested the hypothesis that TRPV4 activation provides a Ca(2+) source necessary for proteolytic disruption of cell-cell or cell-matrix adhesion by matrix metalloproteinases (MMPs) 2 and 9, thus increasing septal barrier permeability. In our study, C57BL/6 or TRPV4(-/-) mouse lungs were perfused with varying doses of the TRPV4 agonist GSK-1016790A (Sigma) and then prepared for Western blot. Lung injury, assessed by increases in lung wet-to-dry weight ratios and total protein levels in the bronchoalveolar lavage fluid, was increased in a dose-dependent fashion in TRPV4(+/+) but not TRPV4(-/-) lungs. In concert with lung injury, we detected increased active MMP2 and MMP9 isoforms, suggesting that TRPV4 can provide the Ca(2+) source necessary for increased MMP2/9 activation. Furthermore, tissue inhibitor of metalloproteinases (TIMP) 2 levels in the TRPV4-injured lungs were decreased, suggesting that TRPV4 activation increases the availability of these active MMPs. We then determined whether MMP2 and MMP9 mediate TRPV4-induced lung injury. Pharmacological blockade (SB-3CT, 1 μM; Sigma) of MMP2 and MMP9 resulted in protection against TRPV4-induced lung injury. We conclude that TRPV4 activation and the subsequent Ca(2+) transient initiates a rapid cascade of events leading to release and activation of the gelatinase MMPs, which then contribute to lung injury.

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A rise of MMP-2 and MMP-9 in bronchoalveolar lavage fluid is associated with acute lung injury after cardiopulmonary bypass in a swine model

Cited by 19 publications

References 28 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

Advances in Understanding of the Pathogenesis of Acute Respiratory Distress Syndrome

Role of MMP2 and MMP9 in TRPV4-induced lung injury

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