Expression of matrix metalloproteinases in pigs with hyperoxia-induced acute lung injury

Gushima, Yasuhiro; Ichikado, Kazuya; Suga, Moritaka; Okamoto, Tatsuya; Iyonaga, Kazuhiro; Sato, Katsutoshi; Miyakawa, Hisako; Ando, Masayuki

doi:10.1183/09031936.01.00049201

Cited by 47 publications

(42 citation statements)

References 29 publications

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“…In hyperoxia-treated pigs, animals developed features of lung injury such as increased wet-to-dry ratio, decreased Pa,O 2 :FI,O 2 ratio and increased bronchoalveolar lavage (BAL) fluid cellularity after 72 h of exposure to 80% oxygen [21]. This was associated with elevated MMP-9 and -2 in BAL after 72 h; parameters of lung injury correlated dose-dependently with BAL MMP-9 concentrations.…”

Section: In Vivo Modelsmentioning

confidence: 80%

“…It was also noted that elevated MMP-2 levels were detected earlier than MMP-9, with a peak at 72 h in contrast to 96 h for MMP-9. Immunohistochemistry localised MMP-9 to neutrophils, macrophages and epithelial cells, whereas MMP-2 mainly localised to alveolar macrophages [21]. Notably, the dominant form of both MMP-2 and-9 detected was the high molecular weight (MW) latent form.…”

Section: In Vivo Modelsmentioning

confidence: 99%

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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: In Vivo Modelsmentioning

confidence: 80%

Section: In Vivo Modelsmentioning

confidence: 99%

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

Davey¹,

2011

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“…In these studies, we concluded that resuscitation with 100% O 2 subsequent to global hypoxia increases cerebral and myocardial injury compared with resuscitation with 21% O 2 . Increased MMP activity was investigated previously in a hyperoxic piglet pulmonary injury model but only after 72 h of exposure (11). Hypoxia-reoxygenation injury triggers MMP production earlier than just hyperoxia (28).…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have investigated the roles of these proteinases in acute lung injury. However, their precise contribution in the development of acute hyperoxic lung injury, including the relationship among MMPs, severity of disease, and pathologic changes, is still unclear (11). MMPs play a role in the increased pulmonary permeability and inflammation after oxidative stress.…”

mentioning

confidence: 99%

Resuscitation of Hypoxic Piglets with 100% O2 Increases Pulmonary Metalloproteinases and IL-8

Munkeby

Børke

Björnland³

et al. 2005

Pediatr Res

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We hypothesized that resuscitation with 100% O 2 compared with 21% O 2 is detrimental to pulmonary tissue. The pulmonary injury was assessed by matrix metalloproteinase (MMP) activity, oxidative stress, IL-8, and histology 2.5 h after resuscitation from a hypoxic state. In pulmonary tissue extracts, MMP activity was analyzed by broad matrix-degrading capacity (total MMP) and zymography. MMP-2 mRNA expression was evaluated by quantitative real-time PCR. Total endogenous antioxidant capacity was measured by the oxygen radical absorbance capacity (ORAC) assay, and IL-8 was analyzed by ELISA technique. In bronchoalveolar lavage (BAL) fluid, MMPs were analyzed by zymography. In pulmonary tissue, pro-and active MMP-2 levels were increased in piglets that were resuscitated with 100% O 2 compared with 21% O 2 . Pro-MMP-9, total MMP activity, and MMP-2 mRNA levels were significantly increased in resuscitated piglets compared with baseline. Net gelatinolytic activity increased in submucosa and blood vessels after 100% O 2 and only in the blood vessels after 21% O 2 . Compared with baseline, ORAC values were considerably lowered in the resuscitated piglets and significantly reduced in the 100% O 2 versus 21% O 2 group. In BAL fluid, both pro-MMP-9 and pro-MMP-2 increased 2-fold in the 100% O 2 group compared with 21% O 2 . Moreover, IL-8 concentration increased significantly in piglets that were resuscitated with 100% O 2 compared with 21% O 2 , suggesting a marked proinflammatory response in the pulmonary tissue. Altogether, these data strongly suggest that caution must be taken when applying pure O 2 to the newborn infant. Traditionally, asphyxiated newborn infants have been resuscitated with 100% O 2 . This recommendation is based mainly on precedent rather than sound evidence. Hyperoxia leads to generation of O 2 free radicals, which have a role in reperfusion injury after asphyxia (1). Naturally, the lung is exposed directly to the highest partial pressure of inspired O 2 , and pulmonary damage, as a result of O 2 exposure, is a serious clinical complication in infants who require high levels of O 2 as treatment (2). It is important not only to provide adequate O 2 consumption in organs but also to prevent further tissue damage during resuscitation caused by reoxygenation injury or O 2 toxicity. This might be achieved by lowering the O 2 concentration during resuscitation. There is therefore an ongoing debate whether to use 21% or 100% O 2 in neonatal resuscitation (3).Matrix metalloproteinases (MMPs) are involved in the pathogenesis of tissue inflammation and wound healing in lung injury (4,5). The role of oxidative stress and its toxic effects on lipids, as well as on disruption of extracellular matrix through up-regulation of MMPs, is well established (6,7). Reduced Received November 19, 2004; accepted February 1, 2005

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“…MMP-9 and MMP-2 appear to be central to the acute phases of ARDS; lung injury models demonstrate increases in their concentrations in BAL fluid following injury [104] (although this study did not report efforts to standardise the assay by measuring total protein content of different samples). 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].…”

Section: Pathogenesis Of Ardsmentioning

confidence: 99%

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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Expression of matrix metalloproteinases in pigs with hyperoxia-induced acute lung injury

Cited by 47 publications

References 29 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

Resuscitation of Hypoxic Piglets with 100% O2 Increases Pulmonary Metalloproteinases and IL-8

Advances in Understanding of the Pathogenesis of Acute Respiratory Distress Syndrome

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