Mechanical Feed-Forward Loops Contribute to Idiopathic Pulmonary Fibrosis

Freeberg, M.A.T.; Perelas, Apostolos; Rebman, J.K.; Phipps, Richard P.; Thatcher, Thomas H.; Sime, Patricia J.

doi:10.1016/j.ajpath.2020.09.008

Cited by 31 publications

(30 citation statements)

References 94 publications

(77 reference statements)

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“…While the ECM was traditionally thought of as an inert substance that represented the end product of fibroblast activation, it is now understood that interactions between ECM and its surrounding cells have a complex interplay in pulmonary fibrosis pathogenesis 129 , 130 , 131 , 132 , 133 . In particular, increases in lung stiffness have been shown to direct cellular activation, differentiation, and migration to further exacerbate the pro-fibrotic environment 134 , 135 , 136 , 137 . In severe cases of ARDS in which the proliferative phase is more exaggerated, decreased compliance of the parenchymal tissue may further activate the fibrotic response leading to the dramatic fibrosis that occurs in a subset of patients.…”

Section: Pathogenesis Of Ards-induced Fibrosismentioning

confidence: 99%

From ARDS to pulmonary fibrosis: the next phase of the COVID-19 pandemic?

Michalski

Kurche

Schwartz

2022

Translational Research

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While the coronavirus disease 19 (COVID-19) pandemic has transformed the medical and scientific communites since it was first reported in late 2019, we are only beginning to understand the chronic health burdens associated with this disease. Although COVID-19 is a multi-systemic disease, the lungs are the primary source of infection and injury, resulting in pneumonia and, in severe cases, acute respiratory distress syndrome (ARDS). Given that pulmonary fibrosis is a well-recognized sequela of ARDS, many have questioned whether COVID-19 survivors will face long-term pulmonary consequences. This review is aimed at integrating our understanding of the pathophysiologic mechanisms underlying fibroproliferative ARDS with our current knowledge of the pulmonary consequences of COVID-19 disease.

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Section: Pathogenesis Of Ards-induced Fibrosismentioning

confidence: 99%

From ARDS to pulmonary fibrosis: the next phase of the COVID-19 pandemic?

Michalski

Kurche

Schwartz

2022

Translational Research

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“…Elevated TGF-β1 levels, coupled with loss of tissue elasticity, further increases FnEDA expression while promoting LTBP-1/FnEDA co-localization, facilitating integrin/LAP engagement and the subsequent creation of tensional strain stimulating the generation of bioactive TGF-β1 (Wynn and Ramalingam, 2012;Freeberg et al, 2021). Progressive ECM stiffness and a TGF-β1-rich microenvironment promotes myofibroblast differentiation and survival while activating the Hippo pathway mechanosensitive transcriptional co-activators YAP and TAZ (Liu et al, 2015;Dupont, 2016;Jorgenson et al, 2017;Misra and Irvine, 2018;Santos and Lagares, 2018;Totaro et al, 2018).…”

Section: Multiple Modes Of Tgf-β1 Activationmentioning

confidence: 99%

The Genomic Response to TGF-β1 Dictates Failed Repair and Progression of Fibrotic Disease in the Obstructed Kidney

Higgins

Tang

Higgins

et al. 2021

Front. Cell Dev. Biol.

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Tubulointerstitial fibrosis is a common and diagnostic hallmark of a spectrum of chronic renal disorders. While the etiology varies as to the causative nature of the underlying pathology, persistent TGF-β1 signaling drives the relentless progression of renal fibrotic disease. TGF-β1 orchestrates the multifaceted program of kidney fibrogenesis involving proximal tubular dysfunction, failed epithelial recovery or re-differentiation, capillary collapse and subsequent interstitial fibrosis eventually leading to chronic and ultimately end-stage disease. An increasing complement of non-canonical elements function as co-factors in TGF-β1 signaling. p53 is a particularly prominent transcriptional co-regulator of several TGF-β1 fibrotic-response genes by complexing with TGF-β1 receptor-activated SMADs. This cooperative p53/TGF-β1 genomic cluster includes genes involved in cellular proliferative control, survival, apoptosis, senescence, and ECM remodeling. While the molecular basis for this co-dependency remains to be determined, a subset of TGF-β1-regulated genes possess both p53- and SMAD-binding motifs. Increases in p53 expression and phosphorylation, moreover, are evident in various forms of renal injury as well as kidney allograft rejection. Targeted reduction of p53 levels by pharmacologic and genetic approaches attenuates expression of the involved genes and mitigates the fibrotic response confirming a key role for p53 in renal disorders. This review focuses on mechanisms underlying TGF-β1-induced renal fibrosis largely in the context of ureteral obstruction, which mimics the pathophysiology of pediatric unilateral ureteropelvic junction obstruction, and the role of p53 as a transcriptional regulator within the TGF-β1 repertoire of fibrosis-promoting genes.

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“…It has been found that ECM stiffness regulates human airway smooth muscle contraction [ 67 ]. However, ECM-dependent forces have received particular attention due to their contribution to the pathogenesis of fibrotic diseases [ 68 , 69 , 70 , 71 ]. Aberrant increases in matrix stiffness result in the activation of lung fibroblasts, excessive ECM deposition, and fibrotic remodeling of the lung tissue [ 66 ], whereas reducing stiffness can partially reverse a stiffness-induced myofibroblast phenotype [ 72 ].…”

Section: Forces On Lung Cells and Tissuementioning

confidence: 99%

“…Excellent reviews have summarized the multiple responses to the different mechanical forces in the lung in detail [ 1 , 70 , 73 , 76 , 77 , 78 , 79 ]. Substantial progress has also been achieved in delineating how cells sense external physical cues and translate them into a cellular response.…”

Section: Forces On Lung Cells and Tissuementioning

confidence: 99%

In Vitro Measurements of Cellular Forces and their Importance in the Lung—From the Sub- to the Multicellular Scale

Kolb

Schundner

Frick

et al. 2021

Life

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Throughout life, the body is subjected to various mechanical forces on the organ, tissue, and cellular level. Mechanical stimuli are essential for organ development and function. One organ whose function depends on the tightly connected interplay between mechanical cell properties, biochemical signaling, and external forces is the lung. However, altered mechanical properties or excessive mechanical forces can also drive the onset and progression of severe pulmonary diseases. Characterizing the mechanical properties and forces that affect cell and tissue function is therefore necessary for understanding physiological and pathophysiological mechanisms. In recent years, multiple methods have been developed for cellular force measurements at multiple length scales, from subcellular forces to measuring the collective behavior of heterogeneous cellular networks. In this short review, we give a brief overview of the mechanical forces at play on the cellular level in the lung. We then focus on the technological aspects of measuring cellular forces at many length scales. We describe tools with a subcellular resolution and elaborate measurement techniques for collective multicellular units. Many of the technologies described are by no means restricted to lung research and have already been applied successfully to cells from various other tissues. However, integrating the knowledge gained from these multi-scale measurements in a unifying framework is still a major future challenge.

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Mechanical Feed-Forward Loops Contribute to Idiopathic Pulmonary Fibrosis

Cited by 31 publications

References 94 publications

From ARDS to pulmonary fibrosis: the next phase of the COVID-19 pandemic?

From ARDS to pulmonary fibrosis: the next phase of the COVID-19 pandemic?

The Genomic Response to TGF-β1 Dictates Failed Repair and Progression of Fibrotic Disease in the Obstructed Kidney

In Vitro Measurements of Cellular Forces and their Importance in the Lung—From the Sub- to the Multicellular Scale

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