TRADITIONALLY, IDIOPATHIC PULMONARY FIBROSIS (IPF) has been seen as an inflammatory disease progressing to pulmonary fibrosis, and consequently, patients have been exposed to corticosteroid therapy. However, anti-inflammatory therapy has failed to have any meaningful impact on this condition. Recent histological studies have challenged the concept that inflammation is central to the pathogenesis of IPF (4). The studies demonstrated that the outcome was determined by the burden of fibroblastic foci, collections of immature fibroblasts, and not the extent of histological inflammation. Consequently, the emerging hypothesis underlying the pathogenesis of IPF is that repeated microscopic injury of alveolar epithelial cells results in dysregulated repair mediated by fibroblastic foci (9). The source of epithelial cell injury has received little attention. It is probable that no single mechanism initiates the disease response in the lung; rather, a combination of injuries potentially contributes to the emergence of IPF. Endogenous herpesviruses may be an important source of injury. Although Epstein-Barr virus (EBV) normally infects the upper respiratory tract, it has also been shown to infect and replicate in the lower respiratory tract (6). Both EBV protein and DNA expression have been identified in lung tissue of patients with IPF (3, 10). In surgically acquired lung tissue, EBV glycoprotein 340/220 and viral capsid antigen viral proteins expressed during the lytic phase of EBV infection have been localized to alveolar epithelial cells (3). The putative role of EBV in the development of IPF has been expanded by findings that the expression of EBV latent membrane protein 1 in alveolar epithelial cells is associated with a poor prognosis in IPF patients (12). Further studies have suggested a pathogenic role for herpes viral infection by demonstrating clinical stability in two patients following oral antiviral therapy (11). However, an association between EBV and IPF does not establish a causal relationship. The acquisition of human lung tissue to explore the proof of concept is clinically difficult because the majority of patients are unsuitable for lung biopsy. Therefore, animal models provide an opportunity to improve our understanding of the relationship between EBV and IPF. Lok et al. (5) have demonstrated that murine -herpesvirus 68 (MHV68), which is biologically equivalent to human EBV, may act as a cofactor in the development of pulmonary fibrosis. BALB/c mice primed with MHV68 and injured with bleomycin, to which they are normally resistant, were seen to develop pulmonary fibrosis. In contrast, there was no evidence of pulmonary fibrosis in those mice exposed to MHV68 in isolation. This suggests that herpesvirus infection alone does not result in pulmonary fibrosis and that an exogenous injury may result in pulmonary fibrosis if the host has been primed with infection. The finding that this infection was not in itself sufficient to induce pulmonary fibrosis in an immunocompetent host emphasizes that the impact of the virus may be influenced by the local cellular environment. The pathological hallmark of IPF is the deposition of extracellular matrix by way of enhanced matrix production or decreased matrix degradation. The deposition of extracellular matrix is propagated through inappropriate activation of both lung epithelial cells and fibroblasts. These cellular alterations are influenced by an imbalance between local mediators of proand antifibrotic activity. This imbalance has been demonstrated in the lungs of IPF patients, as evidenced by enhanced levels of T helper type 2 (Th2) cytokines over their antifibrotic Th1 counterparts (13). Th2 cytokines, such as IL-4 and IL-13, have been demonstrated to activate lung fibroblasts resulting in extracellular matrix deposition. Th1 cytokines, on the other hand, abrogate activation of fibroblasts in IPF. Thus it has been proposed that the predominance of Th2 over Th1 cytokines is a key event in the pathogenesis of IPF. IFN- is a Th1 cytokine that has been implicated in the protective immune response to several herpesviruses. MHV68 is recognized as inducing elevated IFN- during the acute phase of infection, and low-level IFN- is associated with a recrudescence of MHV infection. After MHV68 infection, excessive collagen deposition and splenic atrophy have been observed in IFNR/ mice. This would suggest a cytokine imbalance in favor of IL-4, IL-1, and transforming growth factor (TGF)-1. Consequently, Ebrahimi et al. (1) studied the impact of MHV68 infection in IFN-R/ mice, and they observed the development of pulmonary fibrosis in animals at 14 days following infection.
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Jun 24, 2013
Emily Coffey + 2
Open Access
