Extracellular matrix remodeling in idiopathic pulmonary fibrosis. It is the ‘bed’ that counts and not ‘the sleepers’

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by irreversible fibrosis. Current disease pathogenesis assumes an aberrant wound healing process in response to repetitive injurious stimuli leading to apoptosis of epithelial cells, activation of fibroblasts and accumulation of extracellular matrix (ECM). Particularly, lung ECM is a highly dynamic structure that lies at the core of several physiological and developmental pathways. The scope of this review article is to summarize current knowledge on the role of ECM in the pathogenesis of IPF, unravel novel mechanistic data and identify future more effective therapeutic targets. Areas covered: The exact mechanisms through which lung microenvironment activates fibroblasts and inflammatory cells, regulates profibrotic signaling cascades through growth factors, integrins and degradation enzymes ultimately leading to excessive matrix deposition are discussed. Furthermore, the potential therapeutic usefulness of specific inhibitors of matrix deposition or activators of matrix degradation pathways are also presented. Expert commentary: With a gradually increasing worldwide incidence IPF still present a major challenge in clinical research due to its unknown etiopathogenesis and current ineffective treatment approaches. Today, there is an amenable need for more effective therapeutic targets and ECM components may represent one.

Histological hallmarks and role of Slug/ PIP axis in pulmonary hypertension secondary to pulmonary fibrosis

“…Animals were divided into four groups ( n = 7/group): control (Ctrl), pulmonary fibrosis (PF), pulmonary hypertension (PH), and PF secondary to PH (PF‐PH). At day 0, rats in the PF and PF‐PH groups received an intratracheal instillation of bleomycin (2.5 mg/kg) (Tomos et al , ), whereas the Ctrl and PH groups received a PBS instillation. At day 14, the PH and PF‐PH groups received a subcutaneous injection of monocrotaline (MCT, 60 mg/kg), whereas the Ctrl and PF groups received a subcutaneous injection of PBS (Fig E).…”

“…At the molecular level, the transcription factor Slug, also known as Snai2, has already been implicated in PF (Jayachandran et al , ) where it is expressed by epithelial cells and can participate in extracellular matrix remodeling (Zhang et al , ; Boufraqech et al , ; Coll‐Bonfill et al , ). Slug has also been implicated in chronic obstructive pulmonary disease (Hopper et al , ) as well as in pulmonary arterial hypertension (Ranchoux et al , ; Tomos et al , ), where it is expressed by endothelial cells and participates in endothelial to mesenchymal transition. Nonetheless, the role of Slug has never been investigated in PF‐PH patients to date.…”

Stem cell-based Lung-on-Chips: The best of both worlds?

“…In the lungs, which is a relatively soft tissue with an elastic modulus ranging between 1 and 5 kPa [59], alveolar ECM is composed of a mix of collagen III, IV, V, laminin, fibronectin and elastin [60] whereas the ECM of the large airways includes collagens I, II (cartilage), V, laminin and fibronectin [61]. Further, extensive ECM remodeling has been implicated in many physiological and pathophysiological processes such as wound healing and pulmonary fibrosis [62]. Therefore, the ECM composition used in a model of the lungs must be carefully selected and will depend on the region and the disease state one seeks to model.…”

Hydrogen inhalation attenuated bleomycin‐induced pulmonary fibrosis by inhibiting transforming growth factor‐β1 and relevant oxidative stress and epithelial‐to‐mesenchymal transition

“…Given that the diagnosis of idiopathic pulmonary fibrosis is complex, the search for new biomarkers is a central challenge to advance our understanding of idiopathic pulmonary fibrosis and design future translational research (Inoue, ). Pulmonary fibrosis is characterized by activation of myofibroblasts, which can express α‐smooth muscle actin (α‐SMA) and are associated with the destruction of alveolar capillary units and excessive deposition of extracellular matrix (ECM), such as the excessive accumulation of fibrillar collagens (collagen I, III, V and VI), which, in combination, result in the structural remodelling of pulmonary fibrosis (Kendall & Feghali‐Bostwick, ; Li, Zhao, & Kong, ; Tomos et al., ).…”

“…are associated with the destruction of alveolar capillary units and excessive deposition of extracellular matrix (ECM), such as the excessive accumulation of fibrillar collagens (collagen I, III, V and VI), which, in combination, result in the structural remodelling of pulmonary fibrosis (Kendall & Feghali-Bostwick, 2014;Li, Zhao, & Kong, 2018;Tomos et al, 2017).…”