Virus infection induced pulmonary fibrosis

Abstract

Pulmonary fibrosis is the end stage of a broad range of heterogeneous interstitial lung diseases and more than 200 factors contribute to it. In recent years, the relationship between virus infection and pulmonary fibrosis is getting more and more attention, especially after the outbreak of SARS-CoV-2 in 2019, however, the mechanisms underlying the virus-induced pulmonary fibrosis are not fully understood. Here, we review the relationship between pulmonary fibrosis and several viruses such as Human T-cell leukemia virus (HTLV), Human immunodeficiency virus (HIV), Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Murine γ-herpesvirus 68 (MHV-68), Influenza virus, Avian influenza virus, Middle East Respiratory Syndrome (MERS)-CoV, Severe acute respiratory syndrome (SARS)-CoV and SARS-CoV-2 as well as the mechanisms underlying the virus infection induced pulmonary fibrosis. This may shed new light on the potential targets for anti-fibrotic therapy to treat pulmonary fibrosis induced by viruses including SARS-CoV-2.

Keywords: Mechanisms; Potential anti-fibrotic therapy; Pulmonary fibrosis; SARS-CoV-2; Virus infection.

Fig. 1

Two main pathways of virus-induced injury and pulmonary fibrosis. ① Viral infection causes direct damage to the lung. During most viral infections, the virus causes prompt and direct damage to the lung. Wound healing response is activated at this time, however, the virus induces persistent lung damage and/or abnormal wound-healing, leading to occurrence of pulmonary fibrosis. ② Viral infection causes immune-mediated injury. Virus infection activates the immune system. Macrophages, neutrophils, eosinophils, and Th2 cells aggregate at the site of injury and release a large number of pro-inflammatory and pro-fibrotic cytokines/factors such as TGF-β, TNF-α, MMPs, TIMPs, IL-1, IL-4, IL-5, IL-6, IL-13 and IL-17. The combination of the virus and these factors induces sustained and substantial lung damage, promoting pulmonary fibrosis

Fig. 2

Signaling pathways of pulmonary fibrosis induced by the virus. Virus infection increases the expression of pro-fibrotic and pro-inflammatory cytokines such as TGF-β, TNF-α and IL-6 to promote pulmonary fibrosis. During this process, TGF-β/Smad, ERK and STAT pathways are activated and then upregulate profibrotic cytokines such as TIMP1, PAI-1, CTGF, TGF, TGFBR1, and PGDF. Besides, the decrease in ACE2 upregulates Ang II, leading to increased expression of NF-κB and ROS. NF-κB inhibits fibroblast apoptosis by upregulating Bcl-2 as well as downregulating Bax and caspase 3 to promote pulmonary fibrosis. ROS induces fibroblast migration and α-collagen I synthesis. Moreover, Ang II and TGF-β mutually reinforce each other. Eventually, a large number of myofibroblasts accumulate through EMT and fibroblast transdifferentiation, resulting in extracellular matrix deposition and pulmonary fibrosis