Transforming growth factor‐β: crossroad of glucocorticoid and bleomycin regulation of collagen synthesis in lung fibroblasts

Shukla, Arti; Meisler, Natalie T.; Cutroneo, Kenneth R.

doi:10.1046/j.1524-475x.1999.00133.x

Cited by 46 publications

(31 citation statements)

References 55 publications

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“…Our findings are consistent with the studies of Malizia and colleagues who found that AEC injury with EBV up-regulates TGF-b1 expression in a human cell line (38). TGF-b1 is the most powerful known promoter of extracellular matrix secretion and a number of other fibrogenic processes (41,42), and we expect that gHV-68-induced TGF-b1 production is one mechanism that contributes to the augmentation of fibrosis in our model.…”

Section: Discussionsupporting

confidence: 93%

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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Section: Discussionsupporting

confidence: 93%

Latent Herpesvirus Infection Augments Experimental Pulmonary Fibrosis

Vannella¹,

Luckhardt²,

Wilke³

et al. 2010

Am J Respir Crit Care Med

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“…MCP-1 can stimulate fibroblast deposition of collagen via the up-regulation of TGF-␤ (55). TGF-␤ is known to be up-regulated in the bleomycin model system (56,57), and we anticipate that the same might be true for the FITC model. Thus alterations in TGF-␤ may contribute to the protection seen in the CCR2 Ϫ/Ϫ mice.…”

Section: Ccr2 ϫ/ϫ Mice Are Protected From Pulmonary Fibrosismentioning

confidence: 68%

Protection from Pulmonary Fibrosis in the Absence of CCR2 Signaling

Moore

Paine

Christensen

et al. 2001

The Journal of Immunology

341

292

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Pulmonary fibrosis can be modeled in animals by intratracheal instillation of FITC, which results in acute lung injury, inflammation, and extracellular matrix deposition. We have previously shown that despite chronic inflammation, this model of pulmonary fibrosis is lymphocyte independent. The CC chemokine monocyte-chemoattractant protein-1 is induced following FITC deposition. Therefore, we have investigated the contribution of the main monocyte-chemoattractant protein-1 chemokine receptor, CCR2, to the fibrotic disease process. We demonstrate that CCR2−/− mice are protected from fibrosis in both the FITC and bleomycin pulmonary fibrosis models. The protection is specific for the absence of CCR2, as CCR5−/− mice are not protected. The protection is not explained by differences in acute lung injury, or the magnitude or composition of inflammatory cells. FITC-treated CCR2−/− mice display differential patterns of cellular activation as evidenced by the altered production of cytokines and growth factors following FITC inoculation compared with wild-type controls. CCR2−/− mice have increased levels of GM-CSF and reduced levels of TNF-α compared with FITC-treated CCR2+/+ mice. Thus, CCR2 signaling promotes a profibrotic cytokine cascade following FITC administration.

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“…Recently, a glucocorticoid response element has been described in the human TGF-b1 gene promoter which may inhibit its expression [39]. Furthermore, corticosteroids may impair activation of TGF-b [40], alter its binding characteristics to matrix sites [41], and affect the ligation of TGF-b activator protein to the TGF-b element [42]. These putative anti-fibrotic actions of corticosteroids may complement their known anti-inflammatory effects to retard fibrogenesis and favor the counterregulatory mechanisms of fibrinolysis [43,44].…”

Section: Discussionmentioning

confidence: 99%