Targeting mechanosensitive MDM4 promotes lung fibrosis resolution in aged mice

Qu, Jing; Yang, Shanzhong; Zhu, Yi; Guo, Tao; Thannickal, Victor J.; Zhou, Yong

doi:10.1084/jem.20202033

Cited by 33 publications

(45 citation statements)

References 145 publications

(164 reference statements)

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“…MDM4 is highly expressed in the fibrotic lesions of human IPF and experimental pulmonary fibrosis in aged mice. Our studies provides evidence that mechanosensitive MDM4 is a molecular target with promising therapeutic potential against persistent lung fibrosis associated with aging (Qu et al, 2021). Moreover, ECM stiffness is sensitive to exogenous TGF-β stimulation through inhibiting the interaction of inner nuclear membrane protein LEM domain-containing protein 3 (LEMD3) and SMAD2/3.…”

Section: Matrix Stiffness and Scaffoldingmentioning

confidence: 80%

Idiopathic Pulmonary Fibrosis: An Update on Pathogenesis

et al. 2022

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Idiopathic pulmonary fibrosis (IPF) is a progressive, lethal fibrotic lung disease that occurs primarily in middle-aged and elderly adults. It is a major cause of morbidity and mortality. With an increase in life expectancy, the economic burden of IPF is expected to continuously rise in the near future. Although the exact pathophysiological mechanisms underlying IPF remain not known. Significant progress has been made in our understanding of the pathogenesis of this devastating disease in last decade. The current paradigm assumes that IPF results from sustained or repetitive lung epithelial injury and subsequent activation of fibroblasts and myofibroblast differentiation. Persistent myofibroblast phenotype contributes to excessive deposition of the extracellular matrix (ECM) and aberrant lung repair, leading to tissue scar formation, distortion of the alveolar structure, and irreversible loss of lung function. Treatments of patients with IPF by pirfenidone and nintedanib have shown significant reduction of lung function decline and slowing of disease progression in patients with IPF. However, these drugs do not cure the disease. In this review, we discuss recent advances on the pathogenesis of IPF and highlight the development of novel therapeutic strategies against the disease.

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Section: Matrix Stiffness and Scaffoldingmentioning

confidence: 80%

Idiopathic Pulmonary Fibrosis: An Update on Pathogenesis

et al. 2022

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“…While remarkable efforts have been dedicated to elucidating the origin of myofibroblasts in self-resolving mouse models of lung fibrosis, such as the bleomycin model in young mice ( 12 ), studies investigating myofibroblast persistence in progressive models of lung fibrosis are limited. Prior studies have identified NADPH oxidase 4 (NOX4), mouse double minute 4 homolog (MDM4), and the transcription factor myogenic differentiation 1 (MyoD) as factors that contributed to myofibroblast senescence and apoptosis resistance during persistent lung fibrosis in aged mice ( 11 , 13 – 15 ). Consistent with these findings, we have recently shown that, similarly to IPF, activated fibroblasts accumulated and persisted in the fibrotic lungs of aged mice ( 16 , 17 ), further suggesting that increased myofibroblast survival and/or dysfunctional apoptosis in aging may be responsible for the abnormal myofibroblast accumulation and for the sustained lung fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional analysis of lung fibroblasts identifies PIM1 signaling as a driver of aging-associated persistent fibrosis

et al. 2022

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Idiopathic pulmonary fibrosis (IPF) is an aging-associated disease characterized by myofibroblast accumulation and progressive lung scarring. To identify transcriptional gene programs driving persistent lung fibrosis in aging, we performed RNA-Seq on lung fibroblasts isolated from young and aged mice during the early resolution phase after bleomycin injury. We discovered that, relative to injured young fibroblasts, injured aged fibroblasts exhibited a profibrotic state characterized by elevated expression of genes implicated in inflammation, matrix remodeling, and cell survival. We identified the proviral integration site for Moloney murine leukemia virus 1 (PIM1) and its target nuclear factor of activated T cells-1 (NFATc1) as putative drivers of the sustained profibrotic gene signatures in injured aged fibroblasts. PIM1 and NFATc1 transcripts were enriched in a pathogenic fibroblast population recently discovered in IPF lungs, and their protein expression was abundant in fibroblastic foci. Overexpression of PIM1 in normal human lung fibroblasts potentiated their fibrogenic activation, and this effect was attenuated by NFATc1 inhibition. Pharmacological inhibition of PIM1 attenuated IPF fibroblast activation and sensitized them to apoptotic stimuli. Interruption of PIM1 signaling in IPF lung explants ex vivo inhibited prosurvival gene expression and collagen secretion, suggesting that targeting this pathway may represent a therapeutic strategy to block IPF progression.

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“… 17 , 62 , 63 Moreover, recent preclinical data showed that lung injury can cause non-resolving pulmonary fibrosis through mechanical impairment of lung microenvironment thus suggesting a therapeutic window of opportunity in early SSc-ILD. 64 …”

Section: Discussionmentioning

confidence: 99%

The role of antifibrotic therapies in the treatment of systemic sclerosis–associated interstitial lung disease

Boleto¹,

Avouac

Allanore

2022

Therapeutic Advances in Musculoskeletal

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Systemic sclerosis (SSc) is a rare autoimmune condition with complex pathogenesis characterized by a heterogeneous presentation and different disease courses. Fibrosis of multiple organs including the lungs favored by inflammation and vasculopathy is the hallmark of SSc. SSc-associated interstitial lung disease (SSc-ILD) is common and can be associated with poor outcomes, this complication being the leading cause of death in recent series. Because of its huge heterogeneity, SSc-ILD management can be very challenging. Immunosuppressive therapy has long been used to prevent SSc-ILD progression with modest effects in clinical trials. However, thanks to a better understating of SSc pathogenesis, innovative therapies including antifibrotics are increasingly being developed. The achievement of the Safety and Efficacy of Nintedanib in Systemic SClerosIS (SENSCIS) trial has led to the approval by drug agencies of the first antifibrotic drug for SSc-ILD. In parallel, other antifibrotics are being investigated as possible beneficial therapies in SSc-ILD. An important unmet need remains to clarify the positioning of the various strategies, such as the added value of combination of immunosuppressants and antifibrotic therapies in patients at high risk of progression. Indeed, irreversible lung injury or self-perpetuated progression highlights the concept of a window of opportunity in SSc-ILD patients. Herewith, we provide an overview of the most significant clinical trials with antifibrotic drugs developed in recent years for the management of SSc-ILD and a viewpoint about their positioning in treatment algorithms.

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Targeting mechanosensitive MDM4 promotes lung fibrosis resolution in aged mice

Cited by 33 publications

References 145 publications

Idiopathic Pulmonary Fibrosis: An Update on Pathogenesis

Idiopathic Pulmonary Fibrosis: An Update on Pathogenesis

Transcriptional analysis of lung fibroblasts identifies PIM1 signaling as a driver of aging-associated persistent fibrosis

The role of antifibrotic therapies in the treatment of systemic sclerosis–associated interstitial lung disease

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