Table 2.

Summary of potential mechanisms underlying pulmonary fibrosis induced by viruses

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]