E- and P-Selectins Synergistically Inhibit Bleomycin-Induced Pulmonary Fibrosis

Horikawa, Mayuka; Fujimoto, Manabu; Hasegawa, Minoru; Matsushita, T.; Hamaguchi, Yasuhito; Kawasuji, Ayako; Matsushita, Yukiyo; Fujita, Tomoyuki; Ogawa, Fumihide; Takehara, Kazuhiko; Steeber, Douglas A.; Sato, Shinichi

doi:10.2353/ajpath.2006.060086

Cited by 14 publications

(17 citation statements)

References 39 publications

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“…The roles of P-selectin in the pathogenesis of SSc remain unclear. In lung fibrosis mouse model induced by intratracheal bleomycin administration, P-selectin deficiency did not significantly affect the fibrosis of lungs [48]. On the other hand, another study showed that the loss of P-selectin augmented the fibrosis of both skin and lungs induced by intracutaneous bleomycin injection [30].…”

Section: Discussionmentioning

confidence: 95%

Serum Adhesion Molecule Levels as Prognostic Markers in Patients with Early Systemic Sclerosis: A Multicentre, Prospective, Observational Study

et al. 2014

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ObjectiveTo assess the utility of circulating adhesion molecule levels as a prognostic indicator of disease progression in systemic sclerosis (SSc) patients with early onset disease.MethodsNinety-two Japanese patients with early onset SSc presenting with diffuse skin sclerosis and/or interstitial lung disease were registered in a multicentre, observational study. Concentrations of intercellular adhesion molecule (ICAM) −1, E-selectin, L-selectin, and P-selectin in serum samples from all patients were measured by enzyme-linked immunosorbent asssay (ELISA). In 39 patients, adhesion molecule levels were measured each year for four years. The ability of baseline adhesion molecule levels to predict subsequent progression and severity in clinical and laboratory features were evaluated statistically.ResultsAt their first visit, serum levels of ICAM-1, E-selection, P-selectin were significantly elevated and serum L-selectin levels were significantly reduced in patients with SSc compared with healthy controls. Overall, serum ICAM-1 levels at each time point were significantly inversely associated with the %vital capacity (VC) of the same time and subsequent years by univariate analysis. The initial serum ICAM-1 levels were significantly inversely associated with the %VC at the fourth year by multiple regression analysis. The initial serum P-selectin levels were significantly associated with the health assessment questionnaire disability index (HAQ-DI) at the fourth year by multiple regression analysis. Initial adhesion molecule levels were not significantly associated with other clinical features including skin thickness score. Baseline adhesion molecule levels were not significantly associated with subsequent rate of change of clinical parameters.ConclusionIn patients with SSc, serum levels of ICAM-1 and P-selectin may serve as prognostic indicators of respiratory dysfunction and physical disability, respectively. Further longitudinal studies of larger populations are needed to confirm these findings.

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Section: Discussionmentioning

confidence: 95%

Serum Adhesion Molecule Levels as Prognostic Markers in Patients with Early Systemic Sclerosis: A Multicentre, Prospective, Observational Study

et al. 2014

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“…This may result in differential production of cytokines, which may then directly or indirectly influence the development of dermal sclerosis, pulmonary fibrosis, and inflammatory cell infiltration. Previous studies have demonstrated that loss of L-selectin and/or ICAM-1 function inhibits lung fibrosis induced by intratracheal bleomycin treatment (14), while loss of P-selectin and/or E-selectin function augments it (23). These studies suggest that the mechanisms, by which cell adhesion molecules regulate tissue fibrosis, could be through the regulation of Th1 and Th2 cell infiltration.…”

Section: Discussionmentioning

confidence: 99%

“…BAL cells were prepared as described elsewhere (23). Briefly, bleomycin- or PBS-treated mice were sacrificed and both lungs were excised.…”

Section: Methodsmentioning

confidence: 99%

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Cell Adhesion Molecules Regulate Fibrotic Process via Th1/Th2/Th17 Cell Balance in a Bleomycin-Induced Scleroderma Model

Yoshizaki

Yanaba

Iwata

et al. 2010

The Journal of Immunology

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Mice subcutaneously injected with bleomycin, an experimental model for human systemic sclerosis, develop skin and lung fibrosis, which is mediated by inflammatory cell infiltration. This process is highly regulated by multiple adhesion molecules. To assess the role of adhesion molecules in this pathogenetic process, the bleomycin-induced fibrosis was examined in mice lacking adhesion molecules. In addition, this model does not require antigen sensitization. Therefore, we can exclude the possible role of adhesion molecules on the sensitization phase. L-selectin and/or ICAM-1 deficiency inhibited skin and lung fibrosis with decreased Th2 and Th17 cytokines and increased Th1 cytokines. By contrast, P-selectin deficiency, E-selectin deficiency with or without P-selectin blockade, or PSGL-1 deficiency augmented the fibrosis in parallel with increased Th2 and Th17 cytokines and decreased Th1 cytokines. Furthermore, loss of L-selectin and/or ICAM-1 reduced Th2 and Th17 cell numbers in bronchoalveolar lavage fluid, whereas loss of P-selectin, E-selectin, or PSGL-1 reduced Th1 cell numbers. Moreover, Th1 cells exhibited higher PSGL-1 expression and lower expression of LFA-1, a ligand for ICAM-1, while Th2 and Th17 cells showed higher LFA-1 and lower PSGL-1 expression. This study suggests that L-selectin and ICAM-1 regulate Th2 and Th17 cell accumulation into the skin and lung, leading to the development of fibrosis, and that P-selectin, E-selectin, and PSGL-1 regulate Th1 cell infiltration, resulting in the inhibition of fibrosis.

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“…L-selectin deficiency inhibited lung fibrosis, but P-selectin deficiency and E-selectin deficiency augmented the fibrosis [29]. Another study involving E-selectin −/−, P-selectin −/− mice also revealed an inhibitory role of E-selectins in the development of bleomycin-induced pulmonary fibrosis [36]. Both studies conducted flow cytometric analysis between cell adhesion molecule-deficient mice treated with bleomycin and WT mice and found that loss of cell adhesion molecule function selectively altered the trafficking pattern of fibrogenic Th2 and Th17 cells and anti-fibrogenic Th1 cells to the lung.…”

Section: Discussionmentioning

confidence: 97%

Polymorphisms in SELE Gene and Risk of Coal Workers' Pneumoconiosis in Chinese: A Case-Control Study

Wang

Luo

et al. 2013

PLoS ONE

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BackgroundCoal workers' pneumoconiosis (CWP) is characterized by chronic pulmonary inflammation and fibrotic nodular lesions that usually lead to progressive fibrosis. Inflammation is the first step in the development of CWP. E-selectin, an adhesion molecule, is involved in the development of various inflammatory diseases.MethodsWe investigated the association between the functional polymorphisms in SELE and the risk of CWP in Han Chinese population. Three polymorphisms (T1880C/rs5355, T1559C/rs5368, A16089G/rs4786) in SELE were genotyped and analyzed in a case-control study with 697 CWP cases and 694 controls. The genotyping was based on the TaqMan method with the ABI 7900HT Real Time PCR system.ResultsThe SELE rs5368 CT genotype was associated with a significantly increased risk of CWP (OR = 1.28, 95% CI = 1.02–1.60, P = 0.03) relative to the CC genotype. The statistical analysis of classification and regression tree (CART) and multifactor dimensionality reduction (MDR) were used to predict the interactions among risk factors of CWP. The MDR analysis found that the best interaction model was the two-factor model that contains pack-years smoked and SELE rs5368 genotypes. For non-smokers, the CART analysis showed an increased risk of CWP for carriers of the SELE rs_5368 variant genotype compared with the common genotype (OR = 1.51; 95% CI = 1.11–2.05, P = 0.0069).ConclusionThe results suggest that the T1559C/rs5368 polymorphism and smoking are involved in the susceptibility to CWP. Further studies are warranted to validate these findings.

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E- and P-Selectins Synergistically Inhibit Bleomycin-Induced Pulmonary Fibrosis

Cited by 14 publications

References 39 publications

Serum Adhesion Molecule Levels as Prognostic Markers in Patients with Early Systemic Sclerosis: A Multicentre, Prospective, Observational Study

Serum Adhesion Molecule Levels as Prognostic Markers in Patients with Early Systemic Sclerosis: A Multicentre, Prospective, Observational Study

Cell Adhesion Molecules Regulate Fibrotic Process via Th1/Th2/Th17 Cell Balance in a Bleomycin-Induced Scleroderma Model

Polymorphisms in SELE Gene and Risk of Coal Workers' Pneumoconiosis in Chinese: A Case-Control Study

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