Obstructive lung function decline and IPF

Carone, Mauro; Salerno, Franco; Esquinas, António M.

doi:10.1177/1479972316628534

Cited by 3 publications

(1 citation statement)

References 5 publications

(6 reference statements)

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“…While proliferation and α-SMA expression are accepted markers of activated fibroblasts, fibrotic lesions contribute to patient mortality through airway inflammation, collagen secretion, tissue contraction, and lung stiffening—pathogenic events that hinder the physical process of respiration ( 27 ). Luminex screening of 41 cytokines and chemokines within hydrogel supernatant revealed elevated total cytokine secretion as a function of fiber density over time ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Microengineered 3D pulmonary interstitial mimetics highlight a critical role for matrix degradation in myofibroblast differentiation

et al. 2020

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Fibrosis, characterized by aberrant tissue scarring from activated myofibroblasts, is often untreatable. Although the extracellular matrix becomes increasingly stiff and fibrous during disease progression, how these physical cues affect myofibroblast differentiation in 3D is poorly understood. Here, we describe a multicomponent hydrogel that recapitulates the 3D fibrous structure of interstitial tissue regions where idiopathic pulmonary fibrosis (IPF) initiates. In contrast to findings on 2D hydrogels, myofibroblast differentiation in 3D was inversely correlated with hydrogel stiffness but positively correlated with matrix fibers. Using a multistep bioinformatics analysis of IPF patient transcriptomes and in vitro pharmacologic screening, we identify matrix metalloproteinase activity to be essential for 3D but not 2D myofibroblast differentiation. Given our observation that compliant degradable 3D matrices amply support fibrogenesis, these studies demonstrate a departure from the established relationship between stiffness and myofibroblast differentiation in 2D, and provide a new 3D model for studying fibrosis and identifying antifibrotic therapeutics.

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Section: Resultsmentioning

confidence: 99%

Microengineered 3D pulmonary interstitial mimetics highlight a critical role for matrix degradation in myofibroblast differentiation

et al. 2020

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Effects of mixed heavy metals on obstructive lung function: findings from epidemiological and toxicogenomic data

Nguyen

2023

Environ Geochem Health

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Microengineered 3D pulmonary interstitial mimetics highlight a critical role for matrix degradation in idiopathic pulmonary fibrosis

Matera

DiLillo

Smith

et al. 2020

Preprint

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36Fibrosis is often untreatable and is characterized by aberrant tissue scarring from activated myofibroblasts. 37Although the extracellular matrix becomes increasingly stiff and fibrous during disease progression, how these 38 physical cues impact myofibroblast differentiation in 3D is poorly understood. Here we describe a multicomponent 39 hydrogel that recapitulates the 3D fibrous structure hallmark to the interstitial tissue regions where idiopathic 40 pulmonary fibrosis (IPF) initiates. In contrast to findings on 2D hydrogels, myofibroblast differentiation in 3D was 41 inversely correlated with hydrogel stiffness, but positively correlated with matrix fiber density. Employing a multi-42 step bioinformatics analysis of IPF patient transcriptomes and in vitro pharmacologic screening, we identify matrix-43 metalloprotease activity to be essential for 3D but not 2D myofibroblast differentiation. Given our observation that 44 compliant degradable 3D matrices amply support fibrogenesis, these studies demonstrate a departure from the 45 established relationship between stiffness and myofibroblast differentiation in 2D, and provide a new 3D model for 46 studying fibrosis. 47 48 49 50 51 52 53 54 55 56 57 58 59 Introduction: 60Fibrosis is implicated in nearly 45% of all deaths in the developed world and plays a role in numerous 61 pathologies including pulmonary fibrosis, cardiac disease, atherosclerosis, and cancer (1). In particular, interstitial 62 lung diseases, such as idiopathic pulmonary fibrosis (IPF), are fatal and incurable with a median survival of only 2-63 5 years (2). Often described as dysregulated or incessant wound healing, fibrosis involves persistent cycles of 64 tissue injury and deposition of extracellular matrix (ECM) by myofibroblasts (MFs). These critical cellular mediators 65 of fibrogenesis are primarily derived from tissue resident fibroblasts. MFs drive eventual organ failure through 66 excessive fibrous extracellular matrix deposition, force generation and tissue contraction, and eventual disruption 67 of parenchymal tissue function (1). As organ transplantation remains the only curative option for late-stage disease, 68 effective anti-fibrotic therapeutics that slow MF expansion or even reverse fibrosed tissue remain a major unmet 69 clinical need. Undoubtedly, the limited efficacy of anti-fibrotic drugs at present underscores limitations of existing 70 models for identifying therapeutics, the complexity of the disease, and an incomplete understanding of MF biology. 71A strong correlation between lung tissue stiffening and worse patient outcomes suggests an important role 72 for matrix mechanosensing in fibrotic disease progression (3). Pre-clinical models of fibrosis in mice have supported 73 the link between tissue stiffening and disease progression. However, a precise understanding of how physical cues 74 from the microenvironment influence MF differentiation in vivo is confounded by concurrent structural (eg. collagen 75 density, laminin/elastin degradation) and biochemical (eg. matr...

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Obstructive lung function decline and IPF

Cited by 3 publications

References 5 publications

Microengineered 3D pulmonary interstitial mimetics highlight a critical role for matrix degradation in myofibroblast differentiation

Microengineered 3D pulmonary interstitial mimetics highlight a critical role for matrix degradation in myofibroblast differentiation

Effects of mixed heavy metals on obstructive lung function: findings from epidemiological and toxicogenomic data

Microengineered 3D pulmonary interstitial mimetics highlight a critical role for matrix degradation in idiopathic pulmonary fibrosis

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