Pulmonary fibrosis from molecular mechanisms to therapeutic interventions: lessons from post-COVID-19 patients

Abstract

Pulmonary fibrosis (PF) is characterised by several grades of chronic inflammation and collagen deposition in the interalveolar space and is a hallmark of interstitial lung diseases (ILDs). Recently, infectious agents have emerged as driving causes for PF development; however, the role of viral/bacterial infections in the initiation and propagation of PF is still debated. In this context, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the current coronavirus disease 2019 (COVID-19) pandemic, has been associated with acute respiratory distress syndrome (ARDS) and PF development. Although the infection by SARS-CoV-2 can be eradicated in most cases, the development of fibrotic lesions cannot be precluded; furthermore, whether these lesions are stable or progressive fibrotic events is still unknown. Herein, an overview of the main molecular mechanisms driving the fibrotic process together with the currently approved and newly proposed therapeutic solutions was given. Then, the most recent data that emerged from post-COVID-19 patients was discussed, in order to compare PF and COVID-19-dependent PF, highlighting shared and specific mechanisms. A better understanding of PF aetiology is certainly needed, also to develop effective therapeutic strategies and COVID-19 pathology is offering one more chance to do it. Overall, the work reported here could help to define new approaches for therapeutic intervention in the diversity of the ILD spectrum.

Keywords: Interstitial lung disease; Myofibroblast; Pulmonary fibrosis; SARS-CoV-2 severe acute respiratory syndrome coronavirus 2.

Graphical abstract

Fig. 1

Schematic representation of the immune system involvement in the induction of pulmonaryl fibrosis (PF). Upon endothelial and epithelial injury, cytokines such as tumor growth factor–β (TGF-β), interleukin-6 (IL-6), C-X-C motif chemokine ligand 12 (CXCL12) are released. These cytokines contribute to the activation and recruitment of immune cells (macrophages, SatMs, and neutrophils). T helper 2 (Th2) cells release IL-13 and IL-4 that promote the polarization of macrophages to M2 phenotype (M1: classically activated macrophages phenotype, pro-inflammatory; M2: alternatively activated macrophages phenotype, anti-inflammatory). The M2 cells produce a large amount of TGF-β and the platelet-derived growth factor (PDGF) further contributing to the fibrotic process. Pro-inflammatory cytokines also cause the neutrophil extracellular traps (NETs) formation that contributes to epithelial damage. Green arrow: activation. Black arrow: migration. Light blue arrow: transformation. ECM: extracellular matrix; COL1: collagen type 1; AT1: alveolar epithelial type I cells; AT2: alveolar epithelial type II cells; MSCs: mesenchymal stromal cells; CCL18: C—C motif chemokine ligand 18; ICAM-1: intercellular adhesion molecule-1; VCAM-1: vascular cell adhesion molecule-1.

Fig. 2

Schematic representation of the mechanism regulating myofibroblasts activation in pulmonaryl fibrosis (PF). Soluble mediators such as tumor growth factor–β (TGF-β), interleukin-6 (IL-6), and galectin-3 (Gal-3) promote the transformation of endothelial cells to myofibroblasts (EndMT). Similarly, TGF-β, and IL-6 favour the epithelial-mesenchymal transition (EMT) of alveolar endothelial type 1 (AT1) cells. Another source of myofibroblasts derives from the activation of resident fibroblast and pericytes by TGF-β, the platelet-derived growth factor (PDGF) and fibroblast growth factor 2 (FGF-2) in a process defined fibroblast to myofibroblast transformation (FMT). The activation of TGF-β signalling promotes the formation of myofibroblast from lipofibroblasts. Despite the activation of the peroxisome proliferator-activated receptors-gamma (PPARγ) signalling that could counteract the myofibroblast activation, these pathways are downregulated in PF. The release of IL-8 can also drive the activation of mesenchymal stromal cells (MSCs). The increase of myofibroblast cell bulk causes the over-production of extracellular matrix (ECM).

Fig. 3

Possible characteristic mechanisms of lung fibrosis induced by SARS-CoV-2 infection. The viral infection has a cytolytic effect on alveolar epithelial type II cells (AT2) cells (green cells), the major source of ACE2, resulting in the differentiation of AT2 toward alveolar epithelial type I cells (AT1) pneumocytes and in the increase of AngII, which binds to its receptor AT1R promoting the expression of pro-inflammatory factors such as cytokines as well as increased tPA accumulation in the blood. The pro-inflammatory molecules release contributes to ECM remodelling thus leading to fibrogenesis. The pro-inflammatory cytokines (TNF-α and IL-8) cause the release of KL-6 from AT2 cells. Virus prompts NET formation that in turn reinforce the epithelial damage (yellow cells) and promote the EMT process contributing to myofibroblast accumulation.