Effects of imatinib mesylate on pulmonary allergic vasculitis in a murine model

Suzuki, N.; Sasaki, Nobuyuki; Utsumi, Yu; Nagashima, Hiromi; Nakamura, Yutaka; Yamashita, Masahiro; Yamauchi, Kohei; Sawai, Takashi

doi:10.1111/1756-185x.12075

Cited by 9 publications

(4 citation statements)

References 35 publications

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“…TGF-β not only promotes the proliferation and activation of myofibroblasts but also induces the exaggerated deposition of the extracellular matrix-including collagen and fibronectin in fibrotic tissues [32,33]. We previously reported a marked increase in TGF-β concentration in the BALF of OVA-sensitized mice after OVA exposure [34]. The present study demonstrated that tofacitinib decreased TGF-β concentration in the BALF of the OVA-sensitized mice after OVA exposure, and attenuated vascular remodeling of the pulmonary artery and the proliferation of myofibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Tofacitinib suppressed remodeling of pulmonary eosinophilic vasculitis in a murine model

Matsumoto¹,

Sasaki²,

Nagashima³

et al. 2020

J Transl Sci

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Objective: We examined the effects of tofacitinib on vascular remodeling-including intraluminal myofibroblast proliferation-in a murine model of allergic vasculitis with eosinophil infiltration. Methods:We exposed C57BL/6 mice to ovalbumin (OVA) and aluminum and exposed the positive controls to aerosolized OVA daily for 7 days. We administered tofacitinib (0.1 g/kg) intraperitoneally to the other group of mice in parallel with daily exposure to aerosolized OVA for 7 days. On days 3 and 7, we performed bronchoalveolar lavage (BAL) and excised the lungs for pathological analysis. We determined histological findings of vasculitis and measured concentrations of IL-4, IL-5, IL-6, IL-13, and TGF-β in the BAL fluid (BALF). We then performed a semi-quantitative analysis of pathological changes in the pulmonary arteries according to the severity of vasculitis.Results: In mice treated with tofacitinib, the number of eosinophils in the BALF was reduced significantly when compared with that from control mice treated with just OVA. In the tofacitinib-treated group, TGF-β concentration in the BALF was significantly decreased, pathological scores were significantly reduced, and the number of intraluminal myofibroblasts in the pulmonary arteries was lower than in the control group. Conclusion:Tofacitinib reduced eosinophil infiltration and decreased IL-4, IL-5, IL-6, IL-13, and TGF-β in this murine model of allergic vasculitis with eosinophil infiltration. Our data suggest that tofacitinib suppresses pulmonary vascular remodeling through JAK inhibition.

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Section: Discussionmentioning

confidence: 99%

Tofacitinib suppressed remodeling of pulmonary eosinophilic vasculitis in a murine model

Matsumoto¹,

Sasaki²,

Nagashima³

et al. 2020

J Transl Sci

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“…Amin et al () reported that the number of mast cells was increased at sites of allergic inflammation of patients with atopic and nonatopic asthma. Suzuki et al () and Wambre et al () reported that Ki67‐expressing cells were increased in a mouse model of pulmonary allergic vasculitis and in pollen‐allergic individuals. Okayama & Kawakami () suggested that pharmacologic intervention for a decrease in the proliferation of mast cells could be a strategy for regulation of allergic diseases.…”

Section: Discussionmentioning

confidence: 99%

Phenethyl isothiocyanate decreases thymic stromal lymphopoietin-induced inflammatory reactions in mast cells

et al. 2017

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Phenethyl isothiocyanate (PEITC) has been reported to have anti‐inflammatory and anti‐carcinogenic properties. However, the anti‐inflammatory effects of PEITC on thymic stromal lymphopoietin (TSLP)‐induced inflammatory responses are uncertain. This study evaluates pharmacological activities of PEITC on inflammatory reactions in TSLP‐stimulated mast cells. Human mast cell line HMC‐1 was treated with PEITC (0.04, 0.4, and 4 µM) and subjected to inflammation by TSLP. Our results showed that PEITC significantly attenuated IL‐13 and TNF‐α levels increased by TSLP in HMC‐1. PEITC significantly decreased TSLP‐promoted HMC‐1 proliferation and Ki67 mRNA expression. Protein levels of MDM2 and pSTAT6 increased by TSLP were significantly suppressed by PEITC in HMC‐1. In addition, PEITC significantly enhanced protein levels of cleaved poly ADP‐ribose polymerase and p53 decreased by TSLP. Based on the effects of PEITC on inflammation and proliferation in this study, it is possible that PEITC is a potential candidate to treat mast cells‐mediated inflammatory disorders. Practical applications This report provides strong evidence that Phenethyl isothiocyanate (PEITC) which is a dietary constituent derived from cruciferous vegetables, may be considered an alternative agent for treatment of mast cells‐mediated inflammatory disorders.

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“…Выявлены также дозозависимый протекторный и противовоспалительный эффекты иматиниба при аутоиммунном повреждении легких у мышей [2]. Блокирование острого воспаления показано при аллергическом васкулите с эозинофильной инфильтрацией [11] и аутоиммунном артрите [12]. На модели индуцированного коллагеном артрита иматиниб продемонстрировал способность в микромолярной концентрации блокировать сигнальные пути активации тучных c-Kit + -клеток и высвобождение ФНО-α, цитокиновую продукцию и пролиферацию клеток.…”

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Antitumor proteinkinase inhibitor imatinib may be regarded as a potential correcting agent for COVID-19 associated pulmonary fibrosis

et al. 2021

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Imatinib mesilate (Glivec) is a well-known antitumor target inhibitor of protein tyrosine kinase, which is effective in different cancer types expressing Bcr / Abl and, in particular, in hemoblastosis. A higher interest to imatinib during the COVID-19 epidemic is explained by the fact that cancer patients are one of the COVID-19 risk groups. Moreover, imatinib target mechanism of action, which is effective in cancer, can have a high potential against the most severe COVID-19 complication such as the disease associated pulmonary fibrosis. COVID-19 associated interstitial pulmonary fibrosis develops as an autoimmune process caused by systemic inflammation with atypical (idiopathic) pneumonia resulting from acute respiratory distress syndrome with the tyrosine kinase mechanism of signaling pathway activation and cellular response. Experimental and clinical results showing antifibrotic and dose-related antithrombotic imatinib effect demonstrate perspective use of this antitumor agent to correct COVID-19 associated pneumonia causing a high death rate of patients with COVID-19.The review presents literature data of 2001–2020 discussing pathologic genetic and clinical characteristics of the fibrosis which exacerbates COVID-19 pneumonia in adults. The sequence of the disease processes demonstrates that disease progression with the decreasing oxygen saturation in the peripheral blood intensifies local thrombosis in the lungs. As a result, hypoxia is developing, which is difficult to control and can cause lethal outcome in severe cases. Yet, the conventional antifibrotic and thrombolytic agents can only partially control the process of pneumofibrosis including that of cancer patients. The approximate antifibrotic dose of imatinib 400 mg / day is therapeutic for oncopathology. The antitumor drug registered in many countries and well described side effects and contraindications needs no long-term registration studies for a new indication, therefore, it may be easily prepared for clinical testing.

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Effects of imatinib mesylate on pulmonary allergic vasculitis in a murine model

Cited by 9 publications

References 35 publications

Tofacitinib suppressed remodeling of pulmonary eosinophilic vasculitis in a murine model

Tofacitinib suppressed remodeling of pulmonary eosinophilic vasculitis in a murine model

Phenethyl isothiocyanate decreases thymic stromal lymphopoietin-induced inflammatory reactions in mast cells

Antitumor proteinkinase inhibitor imatinib may be regarded as a potential correcting agent for COVID-19 associated pulmonary fibrosis

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