Pirfenidone and post-Covid-19 pulmonary fibrosis: invoked again for realistic goals

Abstract

Pirfenidone (PFN) is an anti-fibrotic drug with significant anti-inflammatory property used for treatment of fibrotic conditions such as idiopathic pulmonary fibrosis (IPF). In the coronavirus disease 2019 (Covid-19) era, severe acute respiratory syndrome 2 (SARS-CoV-2) could initially lead to acute lung injury (ALI) and in severe cases may cause acute respiratory distress syndrome (ARDS) which is usually resolved with normal lung function. However, some cases of ALI and ARDS are progressed to the more severe critical stage of pulmonary fibrosis commonly named post-Covid-19 pulmonary fibrosis which needs an urgent address and proper management. Therefore, the objective of the present study was to highlight the potential role of PFN in the management of post-Covid-19 pulmonary fibrosis. The precise mechanism of post-Covid-19 pulmonary fibrosis is related to the activation of transforming growth factor beta (TGF-β1), which activates the release of extracellular proteins, fibroblast proliferation, fibroblast migration and myofibroblast conversion. PFN inhibits accumulation and recruitment of inflammatory cells, fibroblast proliferation, deposition of extracellular matrix in response to TGFβ1 and other pro-inflammatory cytokines. In addition, PFN suppresses furin (TGFβ1 convertase activator) a protein effector involved in the entry of SARS-CoV-2 and activation of TGFβ1, and thus PFN reduces the pathogenesis of SARS-CoV-2. Besides, PFN modulates signaling pathways such as Wingless/Int (Wnt/β-catenin), Yes-Associated Protein (YAP)/Transcription Co-Activator PDZ Binding Motif (TAZ) and Hippo Signaling Pathways that are involved in the pathogenesis of post-Covid-19 pulmonary fibrosis. In conclusion, the anti-inflammatory and anti-fibrotic properties of PFN may attenuate post-Covid-19 pulmonary fibrosis.

Keywords: Anti-Fibrotic; Anti-Inflammatory; Covid-19; Pirfenidone; Pulmonary Fibrosis.

Fig. 1

Pathogenesis of post-Covid-19 pulmonary fibrosis: Covid-19 leads to pulmonary fibrosis through iatrogenic pathway, therapy with high oxygen concentration or mechanical ventilation cause oxygen toxicity, which induces the production of reactive oxygen species (ROS) and connective tissue growth factors (CTGFs). The pathological pathway through SARS-CoV-2 induces downregulation of angiotensin-converting enzyme 2 (ACE2) with subsequent activation of AngII, p38 mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3). Together, AngII, MAPK and STAT3 activate the production of transforming growth factor beta1 (TGFβ1). Both AngII and TGFβ1 activate fibroblast activation with subsequent development of pulmonary fibrosis

Fig. 2

Role of Pirfenidone in post-Covid-19 pulmonary fibrosis: Pirfenidone (PFN) has anti-inflammatory effects through inhibition of transforming growth factor beta (TGF-β1), platelet-derived growth factor (PDGF) and pro-inflammatory cytokines, antioxidant effect through inhibition production of reactive oxygen species (ROS) and oxidative stress, antiviral effect through inhibition of cellular furin activity and viral entry, anti-fibrotic effect through suppression of Yes-Associated Protein (YAP)/Transcription Co-Activator PDZ Binding Motif (TAZ), Wingless/Int (Wnt/β-catenin), and Hippo Signaling Pathways. These effects by PFN reduce pro-fibrotic changes and fibroblast activation with subsequent attenuation of post-Covid-19 pulmonary fibrosis