Hyper-responsiveness of IPF/UIP fibroblasts: Interplay between TGFβ1, IL-13 and CCL2

Murray, Lynne A.; Argentieri, Rochelle L.; Farrell, Francis X.; Bracht, Michelle; Sheng, Hai; Whitaker, Brian; Beck, Heena; Tsui, Ping; Cochlin, Karyn; Evanoff, Holly L.; Hogaboam, Cory M.; Das, Anuk

doi:10.1016/j.biocel.2008.02.016

Cited by 135 publications

(126 citation statements)

References 38 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%

“…Excessive accumulation of these inflammatory cells in the lung contributes to severe immunopathology and tissue injury that precipitates tissue remodeling. 8,19,51,52,56,69 The dysregulated anti-influenza T-cell responses that we observed in infected TNF Ϫ/Ϫ or TNF-depleted hosts are likely due in part to reduced T-cell contraction following viral clearance. These results are consistent with studies of intracellular mycobacterial and LCMV infections.…”

Section: Discussionmentioning

confidence: 89%

“…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: Discussionmentioning

confidence: 89%

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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“…Connective tissue growth factor (CTGF), a protein that participates in cell adhesion and migration, angiogenesis and extracellular matrix deposition, has increased expression in the lung fibroblasts of IPF patients 62 and is required for TGF-β-mediated lung fibrosis. CTGF antibody FG-3019 has been found to be effective at attenuating lung collagen deposition in a murine bleomycin model of pulmonary fibrosis (NCT01890265) 63 and is now being tested in a phase 2 randomized double-blind placebo controlled trial to assess its safety and efficacy in treating IPF after an open label study demonstrated no concerns with safety or tolerability (NCT01262001) 64 .…”

Section: Monoclonal Antibodiesmentioning

confidence: 99%

Idiopathic Pulmonary Fibrosis: What Is the Best Treatment?

Wu¹,

Kaner²,

Martinez³

2017

BRN

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Idiopathic pulmonary fibrosis (IPF) is a disease of chronic progressive interstitial pneumonia limited to the lungs. There is growing interest in this disorder as its incidence has increased over time in most countries around the world. This is likely related to an aging population, increased awareness of the disease, and increasingly sensitive imaging technology. Considerable energy has been devoted to creating an improved understanding of its pathogenesis and developing novel therapies. Although dozens of drugs have been studied for the treatment of IPF, only two, pirfenidone and nintedanib, are currently recommended by international guidelines to slow the disease progression. We review the drugs that have been evaluated as IPF therapy over the past three decades, including the currently recommended pirfenidone and nintedanib, note ongoing clinical trials and provide insights into future directions. (BRN Rev. 2017;3:86-101)

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“…It has been hypothesised that this molecule is implicated in the development of fibrosis as fibroblasts from IPF lungs show increase responsiveness to CCL2 and, moreover, when neutralised in the animal model of fibrosis collagen deposition was reduced [70]. CNTO 888, a monoclonal antibody against CCL2, has been investigated in a double-blind, placebo-controlled phase II trial (NCT00786201).…”

Section: Ongoing Clinical Trialsmentioning

confidence: 99%

Pharmacological treatment of idiopathic pulmonary fibrosis: from the past to the future

Αντωνίου

Margaritopoulos

Siafakas

2013

European Respiratory Review

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During the past decade important progress has been made regarding the pathogenesis of idiopathic pulmonary fibrosis (IPF), which is the most devastating form of idiopathic interstitial pneumonia with a median survival of 3 years. The knowledge gained has been used to design multicentre, randomised, placebo-controlled trials in order to investigate agents with different mechanisms of action. Encouraging results have led to licensing of the first IPF-specific drug, pirfenidone. However, the road to successful treatment is still long. The main aim for the future should be the careful design of clinical trials, by choosing the most clinically meaningful end-point and keeping in mind that combination of various agents may be more effective. This approach has been used in the treatment of lung cancer with which IPF presents many similarities. @ERSpublications Progress toward the treatment of IPF and aims for future clinical trials

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Hyper-responsiveness of IPF/UIP fibroblasts: Interplay between TGFβ1, IL-13 and CCL2

Cited by 135 publications

References 38 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

Idiopathic Pulmonary Fibrosis: What Is the Best Treatment?

Pharmacological treatment of idiopathic pulmonary fibrosis: from the past to the future

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