The chronicity of bronchial asthma is attributed to persistent airway inflammation and to a variety of structural changes, or remodelling, that includes smooth muscle and goblet cell hyperplasia.To investigate the mechanisms of airway remodelling, the current authors used an established allergen (ovalbumin; OVA)-driven rodent model (the Brown Norway rat).Brown Norway rats were sensitised to OVA and challenged three times at 5-day intervals to evoke airway remodelling. The effects of an epidermal growth factor (EGF) receptor inhibitor, AG1478, and a cysteinyl leukotriene-1 receptor antagonist, montelukast, on epithelial and airway smooth muscle (ASM) cell proliferation in vivo in response to repeated OVA challenge were tested. Three challenges with leukotriene (LT)D 4 were given, to examine their effects on remodelling with and without AG1478 pretreatment.OVA challenges caused ASM hyperplasia, with an increase in mass, epithelial cell proliferation and goblet cell proliferation. AG1478 prevented the changes, as did montelukast. Multiple OVA challenges increased heparin-binding EGF-like growth factor but not EGF expression by airway epithelium. LTD 4 reproduced the changes in remodelling induced by OVA and this was blocked by AG1478.Allergen-induced airway epithelial and airway smooth muscle remodelling is mediated by cysteinyl leukotrienes via the cysteinyl leukotriene-1 receptor with downstream effects on the epidermal growth factor receptor axis.KEYWORDS: Allergy, inflammation, lung, signal transduction A sthmatic airways often show extensive and complex remodelling [1][2][3][4]. The growth of smooth muscle has the potential to have the most significant pathophysiological consequences through excessive airway narrowing and airway hyperresponsiveness [5,6]. Increase in airway smooth muscle (ASM) in the airways has been associated with the severity of asthma [3,7], and when present in excess in the large airways is associated with mortality [8]. It is known that hyperplasia of smooth muscle in animal models [9][10][11] and both hyperplasia and hypertrophy in airway specimens from human subjects [12,13] contribute to the increase in ASM mass. It has also been proposed that migration of subepithelial myofibroblasts may add to the tissue mass [7].The mechanism of the growth response of muscle is quite uncertain, although several descriptive studies of growth factor expression in human airway tissues have been reported [14][15][16] and many growth factors have been demonstrated to have mitogenic effects on ASM in culture [17][18][19][20]. Cysteinyl (cys)-leukotrienes (LTs) are known to be involved in allergen-induced ASM cell proliferation in vivo [21,22] but in vitro these substances are weak mitogens for ASM [23,24]. In the sensitised mouse, cys-LT 1 receptor (cys-LT 1 R) antagonism prevents an increase in ASM thickening after repeated allergen challenge [25,26]. It is possible that the effects of cys-LTs in vivo are indirect and mediated by altering the expression of or potentiating the effects of tyrosi...

Taken together, our results indicate great potential for the use of S28463 as an antiinflammatory therapeutic agent for the management of chronic asthma.

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SMARCA4-deficient thoracic sarcoma is a rare tumor typically presenting as a mediastinal mass. The prognosis is estimated to be poor, and no effective treatment has been established. We present a case of a 76-year-old man who was diagnosed with SMARCA4-deficient thoracic sarcoma. The provisional diagnosis was carcinoma of unknown primary but subsequently corrected to SMARCA4-deficient thoracic sarcoma based on the panel-based cancer gene screening and immunohistochemistry. Cytotoxic chemotherapy as the first- and second-line did not reveal enough therapeutic effects but third-line therapy using nivolumab showed marked tumor regression, which was sustained. This is the first case report of SMARCA4-deficient thoracic sarcoma showing a good response to nivolumab. Immune checkpoint inhibitor might be therapeutic candidates for this type of tumor.

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Background: Acute exposure to chlorine (Cl 2 ) gas causes epithelial injury and airway dysfunction. γδ T cells are present in the mucosal surface of the airways and may contribute to the injury/repair

Interleukin-13 (IL-13) has been strongly implicated in the pathogenesis of allergic asthma through animal models that have shown that IL-13 is both necessary and sufficient to cause airway hyperresponsiveness (AHR). Airway smooth muscle (ASM) is a primary effector of AHR, and IL-13 increases the responsiveness of ASM, by increasing Ca(2+) release intracellularly, to bronchoconstrictors such as histamine. The mechanisms and signaling pathways mediating this effect are incompletely understood. We have investigated the pathways through which IL-13 regulates the Ca(2+) response to histamine in primary human ASM cell cultures. Functional IL-13 receptors were demonstrated by IL-13-mediated phosphorylation of signal transducer and activator of transcription 6 (STAT6) and mitogen-activated protein kinases (MAPKs). IL-13 increased Ca(2+) responses to histamine. The augmentation of Ca(2+) signaling was not affected by inhibition of STAT6 or p38 MAPK signaling but was prevented by concurrent inhibition of c-jun N-terminal kinase (JNK) and extracellular signal-related kinase (ERK) MAPKs. This inhibition did not affect the IL-13-induced increase in histamine receptors. We conclude that IL-13 induces potentiation of Ca(2+) responses to contractile agonists by affecting mechanisms downstream of receptors. JNK and ERK MAPKs modulate these mechanisms.

Background: The prediction of COVID-19 disease behavior in the early phase of infection is challenging but urgently needed. MuLBSTA score is a scoring system that predicts the mortality of viral pneumonia induced by a variety of viruses, including coronavirus, but the scoring system has not been verified in novel coronavirus pneumonia. The aim of this study was to validate this scoring system for estimating the risk of disease worsening in patients with COVID-19. Methods: This study included the patients who were treated between April 1 st and March 13 th , 2020. The patients were classified into mild, moderate, and severe groups according to the extent of respiratory failure. MuLBSTA score was applied to estimate the risk of disease worsening in each severity group and we validated the utility of the scoring system. Results: A total of 72 patients were analyzed. Among the 46 patients with mild disease, 17 showed disease progression to moderate or severe disease after admission. The model showed a sensitivity of 100% and a specificity of only 34.5% with a cut-off value of 5 points. Among the 55 patients with mild or moderate disease, 6 deteriorated to severe disease, and the model showed a sensitivity of 83.3% and a specificity of 71.4% with a cut-off value of 11 points. Conclusions: This study showed that MuLBSTA score is a potentially useful tool for predicting COVID-19 disease behavior. This scoring system may be used as one of the criteria to identify high-risk patients worsening to life-threatening status.