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Table 2 Summary of potential mechanisms underlying pulmonary fibrosis induced by viruses

From: Virus infection induced pulmonary fibrosis

Virus Animal model Manifestation Potential mechanism References
Human T-cell leukemia virus Transgenic mice with HTLV-I HTLV-I infection causes inflammatory changes in the lung HTLV-I infection leads to clear expression of inflammatory cytokines such as IL-1β, TNF-α and IFN-γ as well as chemokines including RANTES, MCP-1, MIP-1α and IP-10 [9]
Human immunodeficiency virus HIV-1 TG mice HIV related protein gp120 augments α-SMA expression and myofibroblast differentiation in mouse primary lung fibroblasts, promoting pulmonary fibrosis HIV infection increases α-SMA expression and fibroblast-to-myofibroblast transdifferentiation via CXCR4-ERK1/2 signaling pathway [13]
Cytomegalovirus Immunocompetent BALB/c mice MCMV-infected mice had CMV reactivation 2 weeks after CLP. Compared to the control group, the mRNA of TNF-α, IL-1β, KC and MIP-2 significantly increased and pulmonary fibrosis was also developed in the infected mice CMV infection altered the expression of TNF-α, IL-1β, KC and MIP-2 [18]
  Bleomycin BALB/c mice MCMV aggravated pulmonary fibrosis in the bleomycin-treated mice, but not in the control mice CMV infection induces TGF-β secretion from various cells as well as myofibroblast formation [24]
  CMV-positive patients Telomere attrition was exacerbated in CMV-positive individuals CMV reduces telomere length [27]
Murine γ-herpesvirus 68 IFN-γ receptor-deficient mice MHV-68 infection causes epithelial damage, inflammatory response, collagen accumulation and gradually evolves into progressive interstitial fibrosis MHV-68 infection increases TGF-β and IL-13 expression, as well as imbalance of Th1 and Th2 cytokines [33]
Influenza Male albino mice Pulmonary fibrosis occurred after H1N1 infection, and the volume density of fibrous connective tissue in the lung interstitial increased 9–9.4-fold as compared to the control H1N1infection increases TGF-β expression, activates the Smad system and triggers EMT [41]
Avian influenza C57Bl/6 mice Pulmonary interstitial fibrosis was observed on the first day post H5N1 infection. And the histological studies showed necrotic foci and atelectasis, inflammatory infiltrates, bleeding, vascular thrombosis, interstitial and alveolar edema H5N1 infection increases the expression of TNF-α, FGF and EGF, fibroblast proliferation, collagen accumulation and ECM deposition [50, 51]
MERS-COV hDPP4 transgenic mice hDPP4-Tg mice exhibited irregular arrangement of pneumocytes, alveolar septal changes, and inflammatory cell infiltration into the lung. In addition, the lung damage became severe with progressive pulmonary fibrosis, including alveolar septal thickening and macrophage infiltration MERS-COV infection increases the expression of TNF-α, IL-1β, TGF-β, as well as type I and type III collagen [63]
SARS-CoV BALB/c mice SARS-CoV-infected mice presented DAD and hyaline membrane formation Although pulmonary fibrosis was not examined in this model, SARS-CoV infection significantly increased the pro-fibrotic cytokines by regulating RAS system [73]
  C57BL/6J SARS-CoV-infected mice presented pulmonary interstitial thickening, inflammatory infiltration, DAD, and pulmonary fibrosis SARS-CoV infection increases the expression of IL-1β, TNF-α, IL-6, TGF-β, CTGF, PDGF and PAI-1 [75]
SARS-CoV-2 Rhesus SARS-CoV-2-infected rhesus presented interstitial pneumonia. The alveolar interstitial space was greatly expanded by edema, fibrin, macrophages and neutrophils Although pulmonary fibrosis was not examined in this study, SARS-CoV-2 infection increased the expression of collagen, proinflammatory and pro-fibrotic cytokines [91]
  Rhesus SARS-CoV-2-infected rhesus presented interstitial pneumonia. Thickened alveolar walls were observed, with infiltrations of a large number of monocytes and lymphocytes, and a few eosinophils. In the severe lesion area, alveolar wall necrosis, collapse, fibrosis and extensive fibroblast proliferation can be seen No mechanism has been shown in this study [92]