Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF), the most common form of idiopathic interstitial pneumonia, is a progressive, irreversible, and typically lethal disease characterized by an abnormal fibrotic response involving vast areas of the lungs. Given the poor knowledge of the mechanisms underpinning IPF onset and progression, a better understanding of the cellular processes and molecular pathways involved is essential for the development of effective therapies, currently lacking. Besides a number of established IPF-associated risk factors, such as cigarette smoking, environmental factors, comorbidities, and viral infections, several other processes have been linked with this devastating disease. Apoptosis, senescence, epithelial-mesenchymal transition, endothelial-mesenchymal transition, and epithelial cell migration have been shown to play a key role in IPF-associated tissue remodeling. Moreover, molecules, such as chemokines, cytokines, growth factors, adenosine, glycosaminoglycans, non-coding RNAs, and cellular processes including oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, hypoxia, and alternative polyadenylation have been linked with IPF development. Importantly, strategies targeting these processes have been investigated to modulate abnormal cellular phenotypes and maintain tissue homeostasis in the lung. This review provides an update regarding the emerging cellular and molecular mechanisms involved in the onset and progression of IPF.

Molecular mapping of interstitial lung disease reveals a phenotypically distinct senescent basal epithelial cell population

“…Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic lung disease wherein the distal lung tissue is mired in a perpetual wound response due, in part, to defective alveolar epithelial repair ( 1 , 2 ). Various influences contribute to chronic epithelial dysfunction, including genetic factors, age, and exposure to environmental insults including cigarette smoke and viral infection ( 3 , 4 ). Deficits in alveolar epithelial integrity result in compromised gas exchange, barrier dysfunction, inflammation, and excessive deposition of extracellular matrix leading to fibrosis and destruction of lung parenchyma ( 5 , 6 ).…”

EndMT Regulation by Small RNAs in Diabetes-Associated Fibrotic Conditions: Potential Link With Oxidative Stress

“…In addition, concurrently with the loss of typical endothelial markers, such as vascular endothelial cadherin (VE-cadherin), platelet endothelial cell adhesion molecule (PECAM-1), also known as CD31, and von Willebrand Factor (vWF), they acquire the ability to express several mesenchymal markers, such as alpha-smooth muscle actin (α-SMA), smooth muscle protein 22 alpha (SM22α), fibronectin, vimentin, and fibroblast specific protein-1 (FSP-1) ( Dejana et al, 2017 ; Hong et al, 2018 ). EndMT is involved in many chronic and fibrotic disease states and appears to be regulated by several factors ( Evrard et al, 2016 ; Thuan et al, 2018 ; Phan et al, 2020 ). In diabetes, oxidative stress is emerging as an important trigger of the ECs transformation into myofibroblasts and vascular remodeling ( Montorfano et al, 2014 ; Thuan et al, 2018 ).…”

Integrative Analyses Reveal Novel Disease-associated Loci and Genes for Idiopathic Pulmonary Fibrosis

“…Lower body mass index (BMI) and body weight loss seemed to be related to poor outcomes [40]. Altogether, the convergence of genetic and phenotype-level results suggested that metabolic dysregulation might be a critical contributor to the pathogenesis of IPF [41]. Notably, many top correlated phenotypes such as BMI, emphysema, FVC, monocytes, albumin, and neutrophilia appeared to be key IPF survival predictors or clinical markers [42].…”