Macrophage Akt1 Kinase-Mediated Mitophagy Modulates Apoptosis Resistance and Pulmonary Fibrosis

Larson‐Casey, Jennifer L.; Deshane, Jessy; Ryan, Alan J.; Thannickal, Victor J.; Carter, A. Brent

doi:10.1016/j.immuni.2016.01.001

Cited by 333 publications

(375 citation statements)

References 54 publications

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“…Our findings are consistent with a recent publication demonstrating that macrophage-derived TGF-β contributes to fibrosis in WT mice and that macrophages from IPF patients exhibit increased TGF-β expression (40). While our data indicate that macrophage TGF-β promotes fibrosis through a major effect on the lung epithelium in HPS, additional roles for macrophage-derived TGF-β are likely, including activation and differentiation of fibroblasts (40).…”

Section: Discussionsupporting

confidence: 92%

“…For example, BAL macrophages from HPS patients produce excess levels of several cytokines and chemokines ex vivo (9), and our previously published data demonstrate that murine HPS macrophages are primed, exhibiting hyperresponsiveness to LPS, TLR2, and TLR3 agonists (8). Our findings are consistent with a recent publication demonstrating that macrophage-derived TGF-β contributes to fibrosis in WT mice and that macrophages from IPF patients exhibit increased TGF-β expression (40). While our data indicate that macrophage TGF-β promotes fibrosis through a major effect on the lung epithelium in HPS, additional roles for macrophage-derived TGF-β are likely, including activation and differentiation of fibroblasts (40).…”

Section: Discussionsupporting

confidence: 92%

See 1 more Smart Citation

Epithelial-macrophage interactions determine pulmonary fibrosis susceptibility in Hermansky-Pudlak syndrome

Young¹,

Gulleman²,

Short³

et al. 2016

JCI Insight

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Epithelial-macrophage interactions determine pulmonary fibrosis susceptibility in Hermansky-Pudlak syndrome

Young¹,

Gulleman²,

Short³

et al. 2016

JCI Insight

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“…However, in a different set of studies, mice deficient in Parkin were found to be resistant to bleomycin-induced lung fibrosis 195 .…”

Section: Targets and Therapeutic Interventions For Mitochondrial Damagementioning

confidence: 99%

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Mora

Rojas

Pardo

et al. 2017

Nat Rev Drug Discov

290

212

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Idiopathic pulmonary fibrosis (IPF) is a fatal age-associated disease that is characterized by progressive and irreversible scarring of the lung. The pathogenesis of IPF is not completely understood and current therapies are limited to those that reduce the rate of functional decline in patients with mild-to-moderate disease. In this context, new therapeutic approaches that substantially improve the survival time and quality of life of these patients are urgently needed. Our incomplete understanding of the pathogenic mechanisms of IPF and the lack of appropriate experimental models that reproduce the key characteristics of the human disease are major challenges. As ageing is a major risk factor for IPF, age-related cell perturbations such as telomere attrition, senescence, epigenetic drift, stem cell exhaustion, loss of proteostasis and mitochondrial dysfunction are becoming targets of interest for IPF therapy. In this Review, we discuss current and emerging therapies for IPF, particularly those targeting age-related mechanisms, and discuss future therapeutic approaches.Fibrosis as a pathogenic mechanism occurs in numerous organs and diseases. Fibrosis results from abnormal tissue repair and is associated with persistent and/or severe tissue damage and cellular stress. Epithelial and/or endothelial injury caused by various insults triggers interrelated wound-healing pathways to restore homeostasis 1 . Failure to adequately contain or eliminate inciting factors can exacerbate inflammation and chronic woundCorrespondence to A.L.M. anamora@pitt.edu. Competing interests statementThe authors declare competing interests: see Web version for details. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript healing responses, resulting in continued tissue damage and inadequate regeneration and, ultimately, fibrosis 2 . Although their aetiology and causative mechanisms differ, the various fibrotic diseases all have abnormal and exaggerated accumulation of extracellular matrix (ECM) components, mainly fibrillar collagens. The resulting fibrosis disturbs the normal architecture of affected organs, which ultimately leads to their dysfunction and failure. Nearly 45% of deaths in the developed world are attributable to some type of chronic fibroproliferative disease, including idiopathic pulmonary fibrosis (IPF) and end-stage fibrotic liver, kidney and heart disease 2 . The progressive nature of these diseases and the absence of effective treatments mean that a better understanding of the cellular and molecular mechanisms that contribute to the development of fibrosis is needed.Although IPF was originally thought to be an inflammation-driven disorder, clinical trials with a combination of anti-inflammatory drugs (prednisone, azathioprine and N-acetyl-Lcysteine (NAC)), failed to improve outcomes and instead increased mortality 3 . In 2014, two drugs, pirfenidone, a drug with poorly understood mechanisms, and nintedanib, a tyrosine kinase inhibitor, were approved for the treatment of IPF ...

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“…The mechanism of antifibrotic effect by PINK1 may include prevention of cell death by preserving mitochondrial function of pulmonary epithelial cells (96,97). In addition, Parkinson protein 2 E3 ubiquitin protein ligase (PARK2), another key mitophagyassociated molecule, is also implicated in myofibroblast differentiation and proliferation (98), although function of PARK2 on lung fibrosis needs to be further investigated (98,99). It remains unclear whether the observed accumulation of dysfunctional mitochondria and defective mitophagy in the lung of patients with IPF is a consequence of IPF or cause of IPF.…”

Section: Idiopathic Pulmonary Fibrosismentioning

confidence: 99%

Autophagy in Pulmonary Diseases

Nakahira

Porras

Choi

2016

Am J Respir Crit Care Med

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The pathogenesis of pulmonary diseases is often complex and characterized by multiple cellular events, including inflammation, cell death, and cell proliferation. The mechanisms by which these events are regulated in pulmonary diseases remain poorly understood. Autophagy is an essential process for cellular homeostasis and stress adaptation in eukaryotic cells. This highly conserved cellular process involves the sequestration of cytoplasmic components in double-membrane autophagosomes, which are delivered to lysosomes for degradation. The critical roles of autophagy have been demonstrated in a wide range of pathophysiological conditions. Emerging studies have identified that autophagy plays important roles in the pathogenesis of various lung diseases. In addition, autophagy has been shown to selectively degrade subcellular targets, including proteins, organelles, and pathogens. Here, we highlight the recent advances in the molecular regulation and function of autophagy in lung diseases.

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Macrophage Akt1 Kinase-Mediated Mitophagy Modulates Apoptosis Resistance and Pulmonary Fibrosis

Cited by 333 publications

References 54 publications

Epithelial-macrophage interactions determine pulmonary fibrosis susceptibility in Hermansky-Pudlak syndrome

Epithelial-macrophage interactions determine pulmonary fibrosis susceptibility in Hermansky-Pudlak syndrome

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Autophagy in Pulmonary Diseases

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