Insulin-like Growth Factor-I Receptor Blockade Improves Outcome in Mouse Model of Lung Injury

Choi, Jung Eun; Lee, Sung-Soon; Sunde, Donald A.; Huizar, Isham; Haugk, Kathy L.; Thannickal, Victor J.; Vittal, Ragini; Plymate, Stephen R.; Schnapp, Lynn M.

doi:10.1164/rccm.200802-228oc

Cited by 80 publications

(81 citation statements)

References 35 publications

(47 reference statements)

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“…Various cell types expressing IGF-1 are found within the lung, including alveolar macrophages, bronchial epithelial cells, and fibroblasts, hence participation of IGF-I in lung disease pathogenesis has been widely reported (40,41). However, circulating IGF-I levels and pathogenic involvement are still unknown in the context of COPD (42).…”

Section: Discussionmentioning

confidence: 99%

Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence

Takasaka

Araya

Hara

et al. 2014

The Journal of Immunology

164

145

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Cigarette smoke (CS)–induced cellular senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease, and SIRT6, a histone deacetylase, antagonizes this senescence, presumably through the attenuation of insulin-like growth factor (IGF)-Akt signaling. Autophagy controls cellular senescence by eliminating damaged cellular components and is negatively regulated by IGF-Akt signaling through the mammalian target of rapamycin (mTOR). SIRT1, a representative sirtuin family, has been demonstrated to activate autophagy, but a role for SIRT6 in autophagy activation has not been shown. Therefore, we sought to investigate the regulatory role for SIRT6 in autophagy activation during CS-induced cellular senescence. SIRT6 expression levels were modulated by cDNA and small interfering RNA transfection in human bronchial epithelial cells (HBECs). Senescence-associated β-galactosidase staining and Western blotting of p21 were performed to evaluate senescence. We demonstrated that SIRT6 expression levels were decreased in lung homogenates from chronic obstructive pulmonary disease patients, and SIRT6 expression levels correlated significantly with the percentage of forced expiratory volume in 1 s/forced vital capacity. CS extract (CSE) suppressed SIRT6 expression in HBECs. CSE-induced HBEC senescence was inhibited by SIRT6 overexpression, whereas SIRT6 knockdown and mutant SIRT6 (H133Y) without histone deacetylase activity enhanced HBEC senescence. SIRT6 overexpression induced autophagy via attenuation of IGF-Akt-mTOR signaling. Conversely, SIRT6 knockdown and overexpression of a mutant SIRT6 (H133Y) inhibited autophagy. Autophagy inhibition by knockdown of ATG5 and LC3B attenuated the antisenescent effect of SIRT6 overexpression. These results suggest that SIRT6 is involved in CSE-induced HBEC senescence via autophagy regulation, which can be attributed to attenuation of IGF-Akt-mTOR signaling.

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Section: Discussionmentioning

confidence: 99%

Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence

Takasaka

Araya

Hara

et al. 2014

The Journal of Immunology

164

145

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“…Enhanced IGF-1 signalling drives pulmonary fibrosis in mice [239,240], while blocking the IGF-1 receptor counteracted bleomycin-induced lung fibrosis in mice [241]. Accordingly, clinical trials using tyrosine kinase inhibitors to interfere with growth factor signalling [242] have been performed.…”

Section: Dysregulated Nutrient Sensingmentioning

confidence: 99%

Hallmarks of the ageing lung

2015

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Ageing is the main risk factor for major non-communicable chronic lung diseases, including chronic obstructive pulmonary disease, most forms of lung cancer and idiopathic pulmonary fibrosis. While the prevalence of these diseases continually increases with age, their respective incidence peaks at different times during the lifespan, suggesting specific effects of ageing on the onset and/or pathogenesis of chronic obstructive pulmonary disease, lung cancer and idiopathic pulmonary fibrosis. Recently, the nine hallmarks of ageing have been defined as cell-autonomous and non-autonomous pathways involved in ageing. Here, we review the available evidence for the involvement of each of these hallmarks in the pathogenesis of chronic obstructive pulmonary disease, lung cancer, or idiopathic pulmonary fibrosis. Importantly, we propose an additional hallmark, "dysregulation of the extracellular matrix", which we argue acts as a crucial modifier of cell-autonomous changes and functions, and as a key feature of the above-mentioned lung diseases. @ERSpublications Hallmarks of ageing are selecting factors for the pathogenesis of COPD, lung cancer and IPF

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“…In a bleomycin model of ALI and fibrosis, blockade of insulin-like growth factor improved survival and reduced fibrosis (32). Other investigators reported a role for IL-6 in reducing lung injury (33)(34)(35).…”

Section: Pathogenesis Of Ali In Animal Studiesmentioning

confidence: 93%