Dataset Information

Heme oxygenase-1 regulates postnatal lung repair after hyperoxia: role of ?-catenin/hnRNPK signaling.

ABSTRACT: In the newborn, alveolarization continues postnatally and can be disrupted by hyperoxia, leading to long-lasting consequences on lung function. We wanted to better understand the role of heme oxygenase (HO)-1, the inducible form of the rate-limiting enzyme in heme degradation, in neonatal hyperoxic lung injury and repair. Although it was not observed after 3 days of hyperoxia alone, when exposed to hyperoxia and allowed to recover in air (O2/air recovered), neonatal HO-1 knockout (KO) mice had enlarged alveolar spaces and increased lung apoptosis as well as decreased lung protein translation and dysregulated gene expression in the recovery phase of the injury. Associated with these changes, KO had sustained low levels of active ?-catenin and lesser lung nuclear heterogeneous nuclear ribonucleoprotein K (hnRNPK) protein levels, whereas lung nuclear hnRNPK was increased in transgenic mice over-expressing nuclear HO-1. Disruption of HO-1 may enhance hnRNPK-mediated inhibition of protein translation and subsequently impair the ?-catenin/hnRNPK regulated gene expression required for coordinated lung repair and regeneration.

SUBMITTER: Yang G

PROVIDER: S-EPMC3757689 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Heme oxygenase-1 regulates postnatal lung repair after hyperoxia: role of β-catenin/hnRNPK signaling.

Yang Guang G Biswasa Chhanda C Lin Qing Sara QS La Ping P Namba Fumihiko F Zhuang Tiangang T Muthu Manasa M Dennery Phyllis A PA

Redox biology 20130208

In the newborn, alveolarization continues postnatally and can be disrupted by hyperoxia, leading to long-lasting consequences on lung function. We wanted to better understand the role of heme oxygenase (HO)-1, the inducible form of the rate-limiting enzyme in heme degradation, in neonatal hyperoxic lung injury and repair. Although it was not observed after 3 days of hyperoxia alone, when exposed to hyperoxia and allowed to recover in air (O2/air recovered), neonatal HO-1 knockout (KO) mice had e ...[more]

PMID: 24024157

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Project description:BackgroundSilicosis, a progressive inflammatory lung disease attributed mainly to occupational exposure to silica dust, shows loss of lung function even after cessation of exposure. In addition to conventional evaluation methods such as chest X-ray, computed tomography, and spirometry, we identified heme oxygenase (HO)-1, an inducible antioxidant, as a potential biomarker to identify at-risk patients. We found that HO-1 was critical in attenuating the disease progression of silicosis; however, the key signaling pathway has not yet been elucidated. Here, we report the critical pathway after silica exposure, focusing on the role of silica-derived reactive oxygen species (ROS) signaling and its attenuation, which is mediated by HO-1 induction, in vivo and in vitro.MethodsNormal bronchial epithelial cells and a macrophage cell line, as well as a murine silicosis model generated by intratracheal administration of 2.5 mg of crystalline silica, were used in this study. The pathways activated in response to silica exposure, including the mitogen-activated protein kinase (MAPK) signaling pathway, were examined and compared with or without super-induction of HO-1.ResultsThe murine silicosis model was first assessed for the evaluation of activated pathways after silica exposure, focusing on ROS-MAPK activation. In the murine model, increased expression of HO-1 in the lungs was observed after silica-instillation. Moreover, silica-medicated activation of extracellular signal-regulated kinase (ERK) in the lungs was attenuated in response to silica-induced HO-1 upregulation. Activation of other MAPKs, such as p38 and c-Jun N-terminal kinase pathways, after silica exposure was not significantly different irrespective of HO-1 induction. Further in vitro studies showed that 1) silica-induced HO-1 was significantly attenuated by inhibiting ERK activation, and 2) carbon monoxide and bilirubin as final byproducts of HO-1 could inhibit ERK activation. Taken together, silica-induced HO-1 upregulation was mediated by ERK activation, and HO-1 further regulates ERK activation via its final byproducts, carbon monoxide and bilirubin.ConclusionsThis is the first study to demonstrate the regulatory role of HO-1 in silicosis. This finding could contribute to the development of a treatment strategy of monitoring HO-1 levels as a marker of therapeutic intervention.

Dataset Information

Heme oxygenase-1 regulates postnatal lung repair after hyperoxia: role of ?-catenin/hnRNPK signaling.

Publications

Heme oxygenase-1 regulates postnatal lung repair after hyperoxia: role of β-catenin/hnRNPK signaling.

Similar Datasets

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