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Viruses and idiopathic pulmonary fibrosis.

European Respiratory Journal (Impact Factor: 7.13). 08/1997; 10(7):1433-7. DOI: 10.1183/09031936.97.10071433
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    ABSTRACT: Murine gammaherpesvirus-68 (MHV-68) infection in interferon-γ receptor knockout mice (IFN-γR−/−) results in splenic fibrosis and excessive loss of splenocytes. In our present study we found that MHV-68 infection in IFN-γR−/− mice also resulted in fibrosis and atrophy of the mediastinal lymph nodes, interstitial pulmonary fibrosis and fibrotic changes in the liver. Atrophy and cellular depletion of the spleen in IFN-γR−/− was not the result of increased cell death. The loss of splenocytes in IFN-γR−/− mice, which was most evident on day 23 after infection, correlated with an increase in the number of leukocytes in peripheral blood. At the peak of leukocytosis, on day 23 after infection, peripheral blood cells from infected IFN-γR−/− mice were unable to traffic through the fibrosed spleens of IFN-γR−/− mice but were able to enter the spleens of wild-type mice. This indicates that leukocytosis was in part the result of emigration of cells from the spleen and their subsequent exclusion of re-entry at the height of fibrosis. Significant cytokine and chemokine changes were observed in spleens of IFN-γR−/− mice. IFN-γ, tumor necrosis factor-α (TNF-α ), TNF-β, interleukin-1β (IL-1β), transforming growth factor-β1 (TGF-β1), lymphotactin, and MIP-1β were elevated on day 14 after infection whereas chemokines IP-10 and MIG were significantly reduced. These changes suggest a role for dysregulated cytokines and chemokines in severe organ-specific fibrosis with implications for immune-mediated fibrotic disorders.
    American Journal Of Pathology 06/2001; 158(6):2117-2125. DOI:10.1016/S0002-9440(10)64683-4 · 4.60 Impact Factor
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    ABSTRACT: Gammaherpesviruses (γHV) are implicated in the pathogenesis of pulmonary fibrosis in humans and murine models of lung fibrosis, however there is little direct experimental evidence that such viruses induce lung fibrosis in the natural host. The equine γHV EHV 5 is associated with equine multinodular pulmonary fibrosis (EMPF), a progressive fibrosing lung disease in its natural host, the horse. Experimental reproduction of EMPF has not been attempted to date. We hypothesized that inoculation of EHV 5 isolated from cases of EMPF into the lungs of clinically normal horses would induce lung fibrosis similar to EMPF. Neutralizing antibody titers were measured in the horses before and after inoculation with EHV 5. PCR and virus isolation was used to detect EHV 5 in antemortem blood and BAL samples, and in tissues collected postmortem. Nodular pulmonary fibrosis and induction of myofibroblasts occurred in EHV 5 inoculated horses. Mean lung collagen in EHV 5 inoculated horses (80 µg/mg) was significantly increased compared to control horses (26 µg/mg) (p < 0.5), as was interstitial collagen (32.6% ± 1.2% vs 23% ± 1.4%) (mean ± SEM; p < 0.001). Virus was difficult to detect in infected horses throughout the experiment, although EHV 5 antigen was detected in the lung by immunohistochemistry. We conclude that the γHV EHV 5 can induce lung fibrosis in the horse, and hypothesize that induction of fibrosis occurs while the virus is latent within the lung. This is the first example of a γHV inducing lung fibrosis in the natural host.
    PLoS ONE 10/2013; 8(10):e77754. DOI:10.1371/journal.pone.0077754 · 3.53 Impact Factor
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    ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a chronic condition of unknown etiology with an unfavorable outcome from progressively deteriorating respiratory function, leading ultimately to death from respiratory failure. It is characterized by sequential acute lung injury resulting in progressive fixed tissue fibrosis, architectural distortion and loss of function. An excess of profibrotic cytokines and/or a deficiency in antifibrotic cytokines have been implicated in the pathological process as has excessive oxidation. IPF is distinguished from other forms of diffuse pulmonary fibrosis by the presence of the specific histological pattern of usual interstitial pneumonitis. Oral corticosteroids are the usual treatment, but objective response rates are poor and good quality studies do not exist. Other therapies either alone or in combination with corticosteroids are widely used, including azathioprine, colchicine, cyclophosphamide and penicillamine. There is a paucity of good quality information regarding the effectiveness of most noncorticosteroid immunosuppressive agents. Older studies of lesser methodological quality have shown benefits from these drugs, generally when added to corticosteroids. Many were retrospective reviews or uncontrolled, nonrandomized, open-label, prospective studies and often included other histological patterns of disease which are now thought to respond better to immunosuppressive agents. The results of intervention with colchicine and azathioprine have been disappointing when assessed by good quality trials using modern diagnostic criteria. Modern high quality studies are lacking for several agents, notably cyclophosphamide and penicillamine. The older agents may yet prove to be effective but further good quality trials will be necessary to assess these agents adequately. Other new anti-inflammatory, antioxidant, antifibrotic or anticytokine compounds are largely untried or unreported. One trial using interferon-γ-1b showed a significant improvement in pulmonary function but there are concerns regarding the generalizability of this study. Pirfenidone, cyclosporine and acetylcysteine may also prove to be of benefit but current studies are of insufficient quality to allow for any conclusions to be drawn. Currently there is no good evidence to support the routine use of oral corticosteroids, azathioprine, cyclophosphamide, penicillamine, colchicine, cyclosporine or any other immunosuppressive, antifibrotic or immunomodulatory agent in the management of IPF. Interferon, pirfenidone and other new agents may be of benefit but further studies are required. Any recommendations for treatment must therefore be made on an individual and empiric basis. As some other forms of pulmonary fibrosis may respond better to immunosuppressive agents, it remains important to make an accurate diagnosis, by open lung biopsy if necessary.
    American journal of respiratory medicine: drugs, devices, and other interventions 06/2002; 1(3). DOI:10.1007/BF03256611

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