A Role for Matrix Metalloproteinase 9 in IFNγ-Mediated Injury in Developing Lungs

Harijith, Anantha; Choo-Wing, Rayman; Çataltepe, Sule; Yasumatsu, Ryuji; Aghai, Zubair H.; Janér, Joakim; Andersson, Sture; Homer, Robert J.; Bhandari, Vineet

doi:10.1165/rcmb.2010-0058oc

Cited by 56 publications

(56 citation statements)

References 58 publications

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“…The function of MMP9, also called gelatinase B, has been studied in lung development and lung inflammatory diseases such as BPD (3,10). Levels of MMP9 are increased in animal models of BPD (11)(12)(13). 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).…”

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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“…During hyperoxia survival experiments, all NB mice were exposed to 100% O 2 with two lactating dams being used and alternated every 24 hours between room air and hyperoxia to ensure sufficient nutrition (milk) for indicated time points, as previously described (10,11). Rptor flox/flox (B6.…”

Section: Animalsmentioning

confidence: 99%

“…Alveolar size was estimated from the mean chord length of the airspace and septal thickness, as described previously (10,11). …”

Section: Lung Morphometrymentioning

confidence: 99%

Inhibition of Regulatory-Associated Protein of Mechanistic Target of Rapamycin Prevents Hyperoxia-Induced Lung Injury by Enhancing Autophagy and Reducing Apoptosis in Neonatal Mice

Sureshbabu

Syed

Das

et al. 2016

Am J Respir Cell Mol Biol

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Administration of supplemental oxygen remains a critical clinical intervention for survival of preterm infants with respiratory failure. However, prolonged exposure to hyperoxia can augment pulmonary damage, resulting in developmental lung diseases embodied as hyperoxia-induced acute lung injury and bronchopulmonary dysplasia (BPD). We sought to investigate the role of autophagy in hyperoxia-induced apoptotic cell death in developing lungs. We identified increased autophagy signaling in hyperoxia-exposed mouse lung epithelial-12 cells, freshly isolated fetal type II alveolar epithelial cells, lungs of newborn wild-type mice, and human newborns with respiratory distress syndrome and evolving and established BPD. We found that hyperoxia exposure induces autophagy in a Trp53-dependent manner in mouse lung epithelial-12 cells and in neonatal mouse lungs. Using pharmacological inhibitors and gene silencing techniques, we found that the activation of autophagy, upon hyperoxia exposure, demonstrated a protective role with an antiapoptotic response. Specifically, inhibiting regulatory-associated protein of mechanistic target of rapamycin (RPTOR) in hyperoxia settings, as evidenced by wild-type mice treated with torin2 or mice administered (Rptor) silencing RNA via intranasal delivery or Rptor 1/2 , limited lung injury by increased autophagy, decreased apoptosis, improved lung architecture, and increased survival. Furthermore, we identified increased protein expression of phospho-beclin1, light chain-3-II and lysosomalassociated membrane protein 1, suggesting altered autophagic flux in the lungs of human neonates with established BPD. Collectively, our study unveils a novel demonstration of enhancing autophagy and antiapoptotic effects, specifically through the inhibition of RPTOR as a potentially useful therapeutic target for the treatment of hyperoxia-induced acute lung injury and BPD in developing lungs.Keywords: cell death; oxygen; newborn; pulmonary; bronchopulmonary dysplasia Premature infants provided with supplemental oxygen are at higher risk for developing a chronic respiratory disease, bronchopulmonary dysplasia (BPD) (1). BPD occurs in developing lungs resulting in impaired alveolarization and dysregulated vascularization-the pathologic hallmarks (2). Premature infants diagnosed with BPD have diminished pulmonary function and reduced lung capacity as they grow older and up to adulthood (3). This disease represents a common yet complicated clinical issue associated with significant long-term morbidity and mortality (2, 3). Pulmonary-specific oxygen toxicity is This work was supported in part by National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH) grants HL63039 (G.P.) and HL116632 (A.R.), by the Sigrid Jusélius Foundation (S.A.), and by NHLBI/NIH grant HL85103 (V.B.).Author Contributions: Concept and design-A.S. and V.B.; acquisition of data-A.S., M.S., P.D., C.J., G.P., A.R., S.A., R.J.H., and V.B.; data analysis and interpretation-A.S., M.S., P.D., C.J., G.P., A.R., S...

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“…All animal work was approved by the Institutional Animal Care and Use Committee at the Yale University School of Medicine. IFN-g-overexpressing TTG CC10-rtTA/tetracyclinecontrolled transcriptional silencer (tTS)-IFN-g mice were generated in our laboratory (18). The details of the genetic constructs, the methods of microinjection and genotypic evaluation, the inducibility, and the emphysematous and inflammatory phenotype of dual transgenic CC10-rtTA-IFN-g mice have been previously described (16).…”

Section: Transgenic Micementioning

confidence: 99%

“…reported on the potential role of IFN-g in murine and baboon models, as well as in human BPD (18). IFN-g has been shown to induce cyclooxygenase-2 (Cox2) mRNA, protein, and activity in A549 and normal human bronchial epithelial cells (19)(20)(21).…”

mentioning

confidence: 99%

Hyperoxia and Interferon-γ–Induced Injury in Developing Lungs Occur via Cyclooxygenase-2 and the Endoplasmic Reticulum Stress–Dependent Pathway

Choo-Wing

Syed

Harijith

et al. 2013

Am J Respir Cell Mol Biol

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We noted a marked increase in cyclooxygenase-2 (Cox2) and the activation of the endoplasmic reticulum (ER) stress pathway in newborn murine lung on exposure to hyperoxia and IFN-g.We soughtto evaluate Cox2-mediated ER stress pathway activation in hyperoxia-induced and IFN-g-mediated injury in developing lungs. We applied in vivo genetic gain-of-function and genetic/chemical inhibition, as well as in vitro lossof-function genetic strategies. Hyperoxia-induced and IFN-g-mediated impaired alveolarization was rescued by Cox2 inhibition, using celecoxib. The use of small interfering RNA against the ER stress pathway mediator, the C/EBP homologous protein (CHOP; also known as growth arrest and DNA damage-inducible gene 153/GADD153), alleviated cell death in alveolar epithelial cells as well as in hyperoxia-induced and IFNg-mediated murine models of bronchopulmonary dysplasia (BPD). In addition, CHOP siRNA also restored alveolarization in the in vivo models. Furthermore, as evidence of clinical relevance, we show increased concentrations of Cox2 and ER stress pathway mediators in human lungs with BPD. Cox2, via CHOP, may significantly contribute to the final common pathway of hyperoxia-induced and IFN-g-mediated injury in developing lungs and human BPD.Keywords: newborn; oxygen; BPD; CHOP; cell deathIn the developing lung, injury attributable to hyperoxic exposure is an important component in the pathogenesis of bronchopulmonary dysplasia (BPD) (1, 2). The immature human lung during the saccular phase is most commonly exposed to such an exogenous insult, and is predisposed to BPD. The final result is a lung phenotype characterized by fewer and larger simplified alveoli (1-4). Hyperoxia-induced lung injury is characterized by an influx of inflammatory cells, along with endothelial and epithelial cell death (5, 6).Cell death is said to be a key initiator of the process of alveolar simplification. The activation of key caspases (3,8,9) and components of the extrinsic/death receptor and intrinsic/ mitochondrial cell death pathways underlies the molecular mechanisms of cell death (5-7). Another cell-death signaling pathway involves the endoplasmic reticulum (ER), which is the site for the folding and assembly of proteins destined for delivery to the extracellular space, plasma membrane, and the exocytic/endocytic compartments (8, 9). When cells are exposed to ER stress, malfolded or unfolded proteins accumulate in the ER lumen, giving rise to a synonymous term, the unfolded protein response (UPR) (8, 9). ER stress is sensed by three ER-resident transmembrane proteins, specifically, inositol-requiring enzyme-1 a (IRE-a), activating transcription factor-6a (ATF6a), and protein kinase regulated by RNA-like ER kinase (PERK), which are freed from binding immunoglobulin protein (BiP; also known as glucoseregulated protein-78, or GRP78) during ER stress (10). Whereas ER stress-induced cell death signaling can occur via multiple pathways, the pathway (i.e., via PERK) that induces transcription of the proapoptotic factor C/EBP homol...

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A Role for Matrix Metalloproteinase 9 in IFNγ-Mediated Injury in Developing Lungs

Cited by 56 publications

References 58 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

Inhibition of Regulatory-Associated Protein of Mechanistic Target of Rapamycin Prevents Hyperoxia-Induced Lung Injury by Enhancing Autophagy and Reducing Apoptosis in Neonatal Mice

Hyperoxia and Interferon-γ–Induced Injury in Developing Lungs Occur via Cyclooxygenase-2 and the Endoplasmic Reticulum Stress–Dependent Pathway

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