Exacerbation of Established Pulmonary Fibrosis in a Murine Model by Gammaherpesvirus

McMillan, Tracy R.; Moore, Bethany B.; Weinberg, Jason B.; Vannella, Kevin M.; Fields, W. Brad; Christensen, Paul J.; Dyk, Linda F. van; Toews, Galen B.

doi:10.1164/rccm.200708-1184oc

Cited by 99 publications

(115 citation statements)

References 52 publications

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“…MCP-1 has previously been reported to be a major profibrotic chemokine involved in various fibrotic processes, including recruitment of fibrocytes, induction of collagen synthesis, and up-regulation of TGF-␤1 expression in various models. 50,51,[55][56][57][58][59][60][61][63][64][65][66][67][68] Indeed, we observed that MCP-1 responses preceded the responses of fibrogenic growth factor TGF-␤1, 51,52 which were significantly higher in the lung of infected TNF Ϫ/Ϫ lungs and were well correlated with fibrotic tissue remodeling seen in TNF Ϫ/Ϫ lungs at later time points during influenza infection. Thus, depletion of MCP-1 in influenza-infected TNF Ϫ/Ϫ hosts markedly reduced lung immunopathology and tissue remodeling, and such MCP-1 depletion-improved welfare was associated with diminished production of bioactive TGF-␤1.…”

Section: Discussionmentioning

confidence: 84%

“…Compelling evidence suggests that MCP-1 is not only a chemokine for mononuclear cells, but of importance, it is also a profibrotic cytokine capable of direct up-regulation of TGF-␤1 expression [55][56][57][58][59][60][61] and recruitment and induction of collagen synthesis by fibrocytes. 51,[62][63][64][65][66][67][68] Thus, given the dysregulated MCP-1 and its association with heightened TGF-␤1 production seen in influenza-infected TNF Ϫ/Ϫ lungs (Figure 7), we further investigated the role of MCP-1 in heightened immunopathology and fibrotic reaction in the lung of TNF Ϫ/Ϫ mice by means of MCP-1 depletion.…”

Section: Attenuation Of Lung Immunopathology In Influenza-infected Tnmentioning

confidence: 99%

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

Damjanovic

Divangahi

Kugathasan

et al. 2011

The American Journal of Pathology

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Lung immunopathology is the main cause of influenzamediated morbidity and death, and much of its molecular mechanisms remain unclear. Whereas tumor necrosis factor-␣ (TNF-␣) is traditionally considered a proinflammatory cytokine, its role in influenza immunopathology is unresolved. We have investigated this issue by using a model of acute H1N1 influenza infection established in wild-type and TNF-␣-deficient mice and evaluated lung viral clearance, inflammatory responses, and immunopathology. Whereas TNF-␣ was up-regulated in the lung after influenza infection, it was not required for normal influenza viral clearance. However, TNF-␣ deficiency led not only to a greater extent of illness but also to heightened lung immunopathology and tissue remodeling. The severe lung immunopathology was associated with increased inflammatory cell infiltration, anti-influenza adaptive immune responses, and expression of cytokines such as monocyte chemoattractant protein-1 (MCP-1) and fibrotic growth factor, TGF-␤1. Thus, in vivo neutralization of MCP-1 markedly attenuated lung immunopathology and blunted TGF-␤1 production following influenza infection in these hosts. On the other hand, in vivo transgenic expression of MCP-1 worsened lung immunopathology following influenza infection in wild-type hosts. Thus, TNF-␣ is dispensable for influenza clearance; however, different from the traditional belief, this cytokine is critically required for negatively regulating the extent of lung immunopathology during acute influenza infection.

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Section: Discussionmentioning

confidence: 84%

Section: Attenuation Of Lung Immunopathology In Influenza-infected Tnmentioning

confidence: 99%

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

Damjanovic

Divangahi

Kugathasan

et al. 2011

The American Journal of Pathology

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“…In animal models there is now good evidence to show that viral infection can exacerbate established fibrosis and in so doing gives rise to a lesion resembling DAD [37]. However, in a study of 43 individuals suffering an acute exacerbation of IPF, WOOTTON et al [13] failed to clearly identify a viral or other infectious trigger for the acute exacerbation in the vast majority of their subjects.…”

Section: Infection and Acute Exacerbations Of Ipfmentioning

confidence: 99%

The role of infection in the pathogenesis of idiopathic pulmonary fibrosis

Molyneaux

Maher

2013

European Respiratory Review

146

112

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Idiopathic pulmonary fibrosis (IPF) is a progressive, and invariably fatal, condition that is believed to arise in genetically susceptible individuals as a consequence of an aberrant wound-healing response following repetitive alveolar injury. The exact triggers, which initiate the fibrotic process, remain unknown. Infectious agents, including both viruses and bacteria, have the capacity to cause alveolarepithelial cell injury and apoptosis. Relatively few studies have examined the role of infection in IPF. Those that have, point to viruses playing a key role as cofactors in the initiation and progression of IPF. There is also some evidence to suggest that viral infection may be responsible for a proportion of acute exacerbations of IPF. The role played by bacteria in the pathogenesis of IPF is less clear cut. Studies from other respiratory diseases suggest that alterations in the lung microbiome are associated with disease and that these changes influence disease behaviour. Emerging molecular microbiological techniques are making the study of microbial communities in the lung easier. It is hoped that by combining such techniques with the careful longitudinal phenotyping of patients with IPF, it will be possible to elucidate the role played by bacteria and viruses in the pathogenesis of the disease. If infection plays a causal role in IPF then it is possible that therapeutic strategies, utilising currently available antiviral or antibiotic drugs, may be effective in modifying the course of this devastating condition.@ERSpublications Understanding viral and bacterial involvement in IPF could help development of novel therapeutic approaches

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“…Despite this, the lungs of FITC-treated mice infected 14 or 21 days previously with gHV-68 (solid bars) displayed a significant augmentation in collagen levels compared with mock-infected mice treated with FITC (n 5 3-11 per group). latent infection caused a persistent increase in CCL2 and CCL12 protein production (11,24,25). We infected mice intranasally with 5 3 10 4 PFU gHV-68 on Day 0, and the lungs of the infected mice were harvested 15, 24, and 38 d.p.i.…”

Section: Ccl2 and Ccl12 Levels Are Increased In The Lungs Beyond The mentioning

confidence: 99%

“…In addition, we have recently shown that lytic gHV-68 infection can exacerbate established pulmonary fibrosis (11). The mechanisms identified to contribute to lytic virus-induced exacerbation of fibrosis have included Th2 bias, persistent reactivation, alternative activation of macrophages, and fibrocyte recruitment (11)(12)(13).…”

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confidence: 99%

Latent Herpesvirus Infection Augments Experimental Pulmonary Fibrosis

Vannella¹,

Luckhardt²,

Wilke³

et al. 2010

Am J Respir Crit Care Med

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Rationale: No effective treatment exists for idiopathic pulmonary fibrosis, and its pathogenesis remains unclear. Accumulating evidence implicates herpesviruses as cofactors (either initiating or exacerbating agents) of fibrotic lung disease, but a role for latent herpesvirus infection has not been studied. Objectives: To develop a murine model to determine whether latent herpesvirus infection can augment fibrotic responses and to gain insight into potential mechanisms of enhanced fibrogenesis. Methods: Mice were infected with murine gherpesvirus 14 to 70 days before a fibrotic challenge with fluorescein isothiocyanate or bleomycin so that the virus was latent at the time of fibrotic challenge. Measurements were made after viral infection alone or after the establishment of fibrosis. Measurements and Main Results: gHerpesvirus is latent by 14 days post infection, and infection 14 to 70 days before fibrotic challenge augmented fibrosis. Fibrotic augmentation was not dependent on reactivation of the latent virus to a lytic state. Total cell numbers and fibrocyte numbers were increased in the lungs of latently infected mice administered fibrotic challenge compared with mock-infected mice that received fibrotic challenge. Latent infection up-regulates expression of proinflammatory chemokines, transforming growth factor-b1, and cysteinyl leukotrienes in alveolar epithelial cells. Conclusions: Latent gherpesvirus infection augments subsequent fibrotic responses in mice. Enhanced fibrosis is associated with the induction of profibrotic factors and the recruitment of fibrocytes. Our data complement existing human and animal data supporting the hypothesis that gherpesviruses can serve as initiating cofactors in the pathogenesis of pulmonary fibrosis.

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Exacerbation of Established Pulmonary Fibrosis in a Murine Model by Gammaherpesvirus

Cited by 99 publications

References 52 publications

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

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

The role of infection in the pathogenesis of idiopathic pulmonary fibrosis

Latent Herpesvirus Infection Augments Experimental Pulmonary Fibrosis

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