Inhibition of matrix metalloproteinases reduces local and distant organ injury following experimental acute pancreatitis

Muhs, Bart E.; Patel, Sundeep; Yee, Herman; Marcus, Stuart G.; Shamamian, Peter

doi:10.1016/s0022-4804(02)00084-7

Cited by 44 publications

(33 citation statements)

References 21 publications

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“…Investigators demonstrated reduced proteinaceous exudate and neutrophil accumulation in alveoli during acute pancreatitis with i.p. injection of batimastat 48 h prior to initiation of injury [44]. Histological grading of lung injury also improved with pre-administration of batimastat.…”

Section: Hydroxamatesmentioning

confidence: 87%

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

Davey¹,

2011

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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: Hydroxamatesmentioning

confidence: 87%

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

Davey¹,

2011

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“…Destabilization of intercellular connections promotes cellcell slippage, an important contributor to ventricular wall thinning. 9 In animal models of diverse pathologic processes, pharmacologic inhibition of MMPs attenuated acute pancreatitis, 10 improved the strength of intestinal anastomoses, 11 decreased retinal neovascularization, 12 and inhibited ventricular remodeling. 13,14 However, systemic MMP inhibition was associated with severe musculoskeletal pain and tendonitis in clinical trials in patients with metastatic cancer, 15,16 necessitating treatment withdrawal in some cases.…”

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confidence: 99%

Inhibition of Matrix Metalloproteinase Activity by TIMP-1 Gene Transfer Effectively Treats Ischemic Cardiomyopathy

et al. 2004

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Background-Enhanced activity of matrix metalloproteinases (MMPs) has been associated with extracellular matrix degradation and ischemic heart failure in animal models and human patients. This study evaluated the effects of MMP inhibition by gene transfer of TIMP-1 in a rat model of ischemic cardiomyopathy. Methods and Results-Rats underwent ligation of the left anterior descending coronary artery with direct intramyocardial injection of replication-deficient adenovirus encoding TIMP-1 (nϭ8) or null virus as control vector (nϭ8), and animals were analyzed after 6 weeks. Both systolic and diastolic cardiac function was significantly preserved in the TIMP-1 group compared with control animals (maximum left ventricular [LV] pressure: TIMP-1 70Ϯ10 versus control 56Ϯ12 mmHg, PϽ0.05; maximum dP/dt 2697Ϯ842 versus 1622Ϯ527 mmHg/sec, PϽ0.01; minimum dP/dt

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“…The effects of alveolar disruption and protein extravasation into the alveolar space, pathognomic for adult respiratory distress syndrome and pancreatitisassociated lung injury, are promoted by the release of specifi c proteolytic enzymes, matrix metalloproteinases (MMPs), from PMN. Inasmuch as MMP-9 has been evaluated as a local key contributor to pulmonary complications of acute pancreatitis, it has also been identifi ed as a promoter of local disease progression in the pancreas by other groups [7,8] .…”

Section: Discussionmentioning

confidence: 99%

“…During activation, PMN release an array of deleterious proteases [6] . Others and we previously demonstrated that matrix metalloproteinase-9 (MMP-9), one of these proteases, is not only an important factor for the pathogenesis of acute pancreatitis [7,8] , but additionally is involved in the PMN-mediated pulmonary complications of the disease [6] . In the present study we demonstrate that MMP-9 in serum is a valid parameter to differentiate between the mild and severe course of acute pancreatitis in a standardized experimental model and that MMP-9 in rat serum correlates with and precedes pulmonary injury and complications.…”

mentioning

confidence: 99%

MMP-9 in Serum Correlates with the Development of Pulmonary Complications in Experimental Acute Pancreatitis

et al. 2006

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Inhibition of matrix metalloproteinases reduces local and distant organ injury following experimental acute pancreatitis

Cited by 44 publications

References 21 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

Inhibition of Matrix Metalloproteinase Activity by TIMP-1 Gene Transfer Effectively Treats Ischemic Cardiomyopathy

MMP-9 in Serum Correlates with the Development of Pulmonary Complications in Experimental Acute Pancreatitis

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