Role of matrix metalloprotease-9 in hyperoxic injury in developing lung

Chetty, Anne; Cao, Gong-Jie; Severgnini, Mariano; Simon, Amy; Warburton, Rod R.; Nielsen, Heber C.

doi:10.1152/ajplung.00441.2007

Cited by 60 publications

(60 citation statements)

References 46 publications

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“…MMP9 has been shown to be involved in ventilator-and oxygen-induced lung injury and has a potential for destruction of lung matrix and basement membrane (14). MMP9 knockout mice showed increased survival and less important modifications of lung structure after hyperoxia exposure compared to wild-type animals (15). Furthermore, MMP9/TIMP1 ratio has been shown to be elevated in tracheal aspirates of preterm infants who developed BPD (16,17).…”

Section: Discussionmentioning

confidence: 99%

Gene expression profile in newborn rat lungs after two days of recovery of mechanical ventilation

et al. 2015

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Background: Preterm infants having immature lungs often require respiratory support, potentially leading to bronchopulmonary dysplasia (BPD). Conventional BPD rodent models based on mechanical ventilation (MV) present outcome measured at the end of the ventilation period. A reversible intubation and ventilation model in newborn rats recently allowed discovering that different sets of genes modified their expression related to time after MV. In a newborn rat model, the expression profile 48 h after MV was analyzed with gene arrays to detect potentially interesting candidates with an impact on BPD development. Methods: Rat pups were injected P4-5 with 2 mg/kg lipopolysaccharide (LPS). One day later, MV with 21 or 60% oxygen was applied during 6 h. Animals were sacrified 48 h after end of ventilation. Affymetrix gene arrays assessed the total gene expression profile in lung tissue. results: In fully treated animals (LPS + MV + 60% O 2 ) vs. controls, 271 genes changed expression significantly. All modified genes could be classified in six pathways: tissue remodeling/ wound repair, immune system and inflammatory response, hematopoiesis, vasodilatation, and oxidative stress. Major alterations were found in the MMP and complement system. conclusion: MMPs and complement factors play a central role in several of the pathways identified and may represent interesting targets for BPD treatment/prevention.

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Section: Discussionmentioning

confidence: 99%

Gene expression profile in newborn rat lungs after two days of recovery of mechanical ventilation

et al. 2015

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“…These findings provide proof-of-concept evidence that (1) a major site of antioxidant protection during the neonatal period is in the alveolar epithelial cell compartment and (2) alveolar epithelial cell lines can be used as convenient model systems to examine critical events attending O2 lung injury. Although most BPD animal studies have looked at the acute effects of O2 exposure (15,23,24,32), our model of recovery after injury provides valuable insight into the late phase after acute O2 damage. It not only mimics the clinical setting for neonates at risk for developing BPD, but it also gives a timeframe to determine the ideal therapeutic window.…”

Section: Discussionmentioning

confidence: 99%

“…In adult mice exposed to acute O2 for 72 hours, there is proteolytic clearance of SOD3 from the lung during O2, which is believed to contribute to the oxidant-antioxidant imbalance in lung tissue and BALF (12). Another possibility is that the underlying ECM is altered in the setting of O2 due to an imbalance between exaggerated elastin (35) and collagen (22,32) deposition and activation of metalloproteases/collagenases (32,36). Human SOD3 is known to bind to heparan sulfate (37) but has also been shown to bind to ECM components, such as type I collagen (38) and fibulin-5 (39), in mice.…”

Section: Discussionmentioning

confidence: 99%

Superoxide Dismutase 3 Dysregulation in a Murine Model of Neonatal Lung Injury

Poonyagariyagorn

Metzger

Dikeman

et al. 2014

Am J Respir Cell Mol Biol

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Bronchopulmonary dysplasia (BPD), a common chronic respiratory disease that occurs after premature birth, is believed to be secondary to oxidative damage from hyperoxia and inflammation, which leads to impaired alveolar formation and chronic lung dysfunction. We hypothesized that extracellular superoxide dismutase (SOD)3, an antioxidant uniquely targeted to the extracellular matrix (ECM) and alveolar fluid, might have a different response (downregulation) to hyperoxic injury and recovery in room air (RA), thereby contributing to the persistent airspace injury and inflammation. We used a murine BPD model using postnatal hyperoxia (O2) (4 or 5 d) followed by short-term recovery (14 d) in RA, which mimics the durable effects after injury during alveolar development. This was associated with significantly increased mRNA expression for antioxidant genes mediated by nuclear factor erythroid 2-related factor (Nrf2) in the O2 (n = 4) versus RA group (n = 5). SOD3, an Nrf2-independent antioxidant, was significantly reduced in the O2-exposed mice compared with RA. Immunohistochemistry revealed decreased and disrupted SOD3 deposition in the alveolar ECM of O2-exposed mice. Furthermore, this distinct hyperoxic antioxidant and injury profile was reproducible in murine lung epithelial 12 cells exposed to O2.Overexpression of SOD3 rescued the injury measures in the O2-exposed cells. We establish that reduced SOD3 expression correlates with alveolar injury measures in the recovered neonatal hyperoxic lung, and SOD3 overexpression attenuates hyperoxic injury in an alveolar epithelial cell line. Such findings suggest a candidate mechanism for the pathogenesis of BPD that may lead to targeted interventions.

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“…Investigation of hyperoxic injury in the developing lung using MMP-9 knockout mice demonstrated that deficient MMP-9 seems to abrogate the BPD-like features generated by hyperoxia in wild-type controls [51]. Lung injury induced by intratracheal instillation of immunoglobulin G in mice was shown to be reduced in MMP-9 knockouts compared with wild-type controls [52].…”

Section: Other Inhibitorsmentioning

confidence: 99%

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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Role of matrix metalloprotease-9 in hyperoxic injury in developing lung

Cited by 60 publications

References 46 publications

Gene expression profile in newborn rat lungs after two days of recovery of mechanical ventilation

Gene expression profile in newborn rat lungs after two days of recovery of mechanical ventilation

Superoxide Dismutase 3 Dysregulation in a Murine Model of Neonatal Lung Injury

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

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