Viral infection and aging as cofactors for the development of pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown origin and progression that primarily affects older adults. Accumulating clinical and experimental evidence suggests that viral infections may play a role, either as agents that predispose the lung to fibrosis or exacerbate existing fibrosis. In particular, herpesviruses have been linked with IPF. This article summarizes the evidence for and against viral cofactors in IPF pathogenesis. In addition, we review mechanistic studies in animal models that highlight the fibrotic potential of viral infection, and explore the different mechanisms that might be responsible. We also review early evidence to suggest that the aged lung may be particularly susceptible to viral-induced fibrosis and make recommendations for future research directions. Keywordscollagen; Epstein-Barr virus; gammaherpesvirus; lung; murine gammaherpesvirus-68; senescence Idiopathic pulmonary fibrosis: clinical presentation & potential causesIdiopathic pulmonary fibrosis (IPF) and its histologic presentation, usual interstitial pneumonia (UIP), is a chronic parenchymal disorder of the lungs that is characterized by progressive loss of pulmonary function, probably due to fibroblast hyperplasia and excess collagen deposition destroying normal lung tissue. It is thought to occur after some inciting event causes injury to the alveolar surface and leads to dysregulated repair. This dysfunctional repair is characterized by loss of type 1 alveolar cells and expansion of type 2 cells [1], induction of proinflammatory cytokines with a Th2 predominance [2], the synthesis of profibrotic factors such as TGF-β1 [2,3], alterations in eicosanoid regulation skewing the balance towards leukotriene synthesis and away from prostaglandin synthesis [4,5], decreased plasminogen activation [6], the recruitment of bone marrow-derived fibrocytes [7][8][9], the occurrence of epithelial-mesenchymal transition [10][11][12], fibroblast proliferation, the transformation of these fibroblasts to α-smooth muscle actin producing †

Negative Regulation of Lung Inflammation and Immunopathology by TNF-α during Acute Influenza Infection

“…[3][4][5][6][7][8][9][10][11] TNF-␣, a classical proinflammatory cytokine, has recently been shown to play anti-inflammatory and antifibrotic roles in various models. [32][33][34][35][36][37][38][39][40][41][42][43] However, whether TNF-␣ plays an immunoregulatory role during influenza infection remains unclear.…”

“…1,2 It is now well established that lung immunopathology is one of the main causes of influenzarelated morbidity and mortality. [3][4][5][6][7][8][9][10][11] Influenza viruses are negative-stranded, enveloped RNA viruses belonging to the family Orthomyxoviridae that preferentially infect and replicate in bronchial epithelial cells. 7 Both innate and adaptive immune responses are key players in the host defense against influenza.…”

Pulmonary fibrosis: patterns and perpetrators

“…The vulnerable alveolar epithelium in IPF Several lines of evidence have emerged implicating a combination of environmental, age-related, and genetic factors that coalesce to create an alveolar epithelium that is susceptible to injury from either unknown endogenous factors or exogenous insults such as viral infection or microaspiration (25)(26)(27). The mutations in surfactant proteins C and A2 that have been identified in familial pulmonary fibrosis result in abnormalities in surfactant protein folding (28).…”

Emerging evidence for endoplasmic reticulum stress in the pathogenesis of idiopathic pulmonary fibrosis

“…Aging has long been considered a central player in many chronic diseases and recently has been implicated as a major cofactor in the development of IPF (12,69), with evidence suggesting that the aged lung is at greater risk for the development of lung fibrosis following injury (57,69). Interestingly, aging leads to both a decline in protein folding ability in cells and in impaired ability of UPR responses to maintain cellular homeostasis in the setting of ER stress (54,55).…”