Differential role of regulatory T cells in early and late stages of pulmonary fibrosis

Boveda-Ruiz, Daniel; D’Alessandro-Gabazza, Corina N.; Toda, Masaaki; Takagi, Takehiro; Naito, Makoto; Matsushima, Yuki; Μatsumoto, Takahiro; Kobayashi, Tetsu; Gil-Bernabe, Paloma; Chelakkot-Govindalayathil, Ayshwarya-Lakshmi; Miyake, Yohei; Yasukawa, Atsushi; Morser, John; Taguchi, Osamu; Gabazza, Esteban C.

doi:10.1016/j.imbio.2012.05.020

Cited by 81 publications

(68 citation statements)

References 31 publications

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“…Patients with IPF and collagen vascular disease-associated pulmonary fibrosis demonstrate a reduced number and function of Tregs in BAL fluid and peripheral blood, compared with controls, suggesting that Tregs may play a role in fibroproliferation (27). However, conflicting data in the literature have emerged regarding Tregs in animal models of pulmonary fibrosis (31)(32)(33)(34), suggesting that the role of Tregs in regulating fibroproliferation may be both context-specific and site-specific. To our knowledge, the role of Tregs in the fibroproliferative response to ALI has not been described.…”

Section: Discussionmentioning

confidence: 99%

Regulatory T Cells Reduce Acute Lung Injury Fibroproliferation by Decreasing Fibrocyte Recruitment

Garibaldi

D’Alessio

Mock

et al. 2013

Am J Respir Cell Mol Biol

155

139

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Acute lung injury (ALI) causes significant morbidity and mortality. Fibroproliferation in ALI results in worse outcomes, but the mechanisms governing fibroproliferation remain poorly understood. Regulatory T cells (Tregs) are important in lung injury resolution. Their role in fibroproliferation is unknown. We sought to identify the role of Tregs in ALI fibroproliferation, using a murine model of lung injury. Wild-type (WT) and lymphocyte-deficient Rag-1 2/2 mice received intratracheal LPS. Fibroproliferation was characterized by histology and the measurement of lung collagen. Lung fibrocytes were measured by flow cytometry. To dissect the role of Tregs in fibroproliferation, Rag-1 2/2 mice received CD4 1 CD25 1 (Tregs) or CD4 1 CD252 Tcells (non-Tregs) at the time of LPS injury. To define the role of the chemokine (C-X-C motif) ligand 12 (CXCL12)-CXCR4 pathway in ALI fibroproliferation, Rag-1 2/2 mice were treated with the CXCR4 antagonist AMD3100 to block fibrocyte recruitment. WT and Rag-1 2/2 mice demonstrated significant collagen deposition on Day 3 after LPS. WT mice exhibited the clearance of collagen, but Rag-1 2/2 mice developed persistent fibrosis. This fibrosis was mediated by the sustained epithelial expression of CXCL12 (or stromal cell-derived factor 1 [SDF-1]) that led to increased fibrocyte recruitment. The adoptive transfer of Tregs resolved fibroproliferation by decreasing CXCL12 expression and subsequent fibrocyte recruitment. Blockade of the CXCL12-CXCR4 axis with AMD3100 also decreased lung fibrocytes and fibroproliferation. These results indicate a central role for Tregs in the resolution of ALI fibroproliferation by reducing fibrocyte recruitment along the CXCL12-CXCR4 axis. A dissection of the role of Tregs in ALI fibroproliferation may inform the design of new therapeutic tools for patients with ALI.Keywords: acute lung injury; fibroproliferative ARDS; fibrocytes; regulatory T cells; lung injury resolution Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) affect 190,000 individuals in the United States each year, accounting for 75,000 deaths (1). The only treatment that improves outcomes involves a lung-protective strategy in patients on mechanical ventilation (2). Mortality from ALI/ARDS remains as high as 44% (3).ALI/ARDS is divided into an exudative phase marked by edema fluid, hyaline membrane formation, and neutrophilic infiltration, followed in some patients by a fibroproliferative phase (4). Fibroproliferation is part of the normal repair response, and is characterized by the intra-alveolar accumulation of fibroblasts and collagen deposition. If this process is ineffective or continues unabated, patients may develop fibrosis (5). Longer durations of ARDS correspond to increased lung collagen and fibrosis, and portend worse outcomes (6). Fibroproliferative changes on biopsy and computed tomography predict mortality (7,8). The determinants of prolonged fibroproliferation and factors that govern its resolution remain poorly understood.The fibroblast is a key cell ...

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Section: Discussionmentioning

confidence: 99%

Regulatory T Cells Reduce Acute Lung Injury Fibroproliferation by Decreasing Fibrocyte Recruitment

Garibaldi

D’Alessio

Mock

et al. 2013

Am J Respir Cell Mol Biol

155

139

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“…Baba et al (20), Liu et al (14), and Tanaka et al (21) also demonstrated that Treg depletion by administration of the anti-CD25 antibody PC 61 can suppress Tregs (22). We identified a preventive role for Treg depletion in radiation-induced pulmonary fibrosis, by decreasing alveolar septal thickening and collagen deposition in lung tissues of mice exposed to irradiation.…”

Section: Discussionmentioning

confidence: 51%

Regulatory T Cells Promote β-Catenin–Mediated Epithelium-to-Mesenchyme Transition During Radiation-Induced Pulmonary Fibrosis

Xiong

Pan

et al. 2015

International Journal of Radiation Oncology*Biology*Physics

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“…Of all the mechanisms involved, the role of immunologically-mediated inflammation is the most extensively studied, and while fibrosis may seem to be the direct consequence of this chronic inflammation, it is just as conceivable that inflammation and fibrosis develop independently, though with mutually interacting mechanisms [10]. There is considerable heterogeneity in observations, however numerous animal models and humans studies have shed light on the effect of the Th cell profile (Th2, Th9, Th17, Th22) [11][12][13][14], T regulatory cells [15,16] and T cell-mediated cytotoxicity (e.g., Fas-mediated and perforin/granzyme pathways) [17][18][19].…”

Section: Pathogenesismentioning

confidence: 99%

Fibrotic hypersensitivity pneumonitis

Pérez

Brown

2014

Curr Respir Care Rep

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Fibrotic hypersensitivity pneumonitis (FHP) is a specific form of HP defined by chest imaging evidence or pathologic evidence of fibrosis or scarring. Fibrotic HP appears to be irreversible, is often progressive and frequently indistinguishable from other forms of chronic fibrosing interstitial lung diseases (ILD), in particular idiopathic pulmonary fibrosis (IPF). Accurate diagnosis is a challenge given the diverse and often nonspecific clinicoradiologic patterns, heterogenous clinical course, and a frequent lack of a readily recognizable temporal relationship between exposure to an inciting antigen (IA) and symptoms in more than half of the patients. This chapter focuses on the clinical features, diagnostic evaluation and management of FHP.

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Differential role of regulatory T cells in early and late stages of pulmonary fibrosis

Cited by 81 publications

References 31 publications

Regulatory T Cells Reduce Acute Lung Injury Fibroproliferation by Decreasing Fibrocyte Recruitment

Regulatory T Cells Reduce Acute Lung Injury Fibroproliferation by Decreasing Fibrocyte Recruitment

Regulatory T Cells Promote β-Catenin–Mediated Epithelium-to-Mesenchyme Transition During Radiation-Induced Pulmonary Fibrosis

Fibrotic hypersensitivity pneumonitis

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