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Abstract The development of chronic obstructive pulmonary disease (COPD) pathogenesis remains unclear, but emerging evidence supports a crucial role for inducible bronchus‐associated lymphoid tissue (iBALT) in disease progression. Mechanisms underlying iBALT generation, particularly during chronic CS exposure, remain to be defined. Oxysterol metabolism of cholesterol is crucial to immune cell localization in secondary lymphoid tissue. Here, we demonstrate that oxysterols also critically regulate iBALT generation and the immune pathogenesis of COPD. In both COPD patients and cigarette smoke (CS)‐exposed mice, we identified significantly upregulated CH25H and CYP7B1 expression in airway epithelial cells, regulating CS‐induced B‐cell migration and iBALT formation. Mice deficient in CH25H or the oxysterol receptor EBI2 exhibited decreased iBALT and subsequent CS‐induced emphysema. Further, inhibition of the oxysterol pathway using clotrimazole resolved iBALT formation and attenuated CS‐induced emphysema in vivo therapeutically. Collectively, our studies are the first to mechanistically interrogate oxysterol‐dependent iBALT formation in the pathogenesis of COPD, and identify a novel therapeutic target for the treatment of COPD and potentially other diseases driven by the generation of tertiary lymphoid organs.

Hypoxia-inducible factors (HIF) are among the targeted treatment strategies with increasing promise in lung cancer, and are known to play a role in tumour growth and other oncogenic properties in cancer cells. Therefore, there is an urgent need for selective HIF inhibitors that can provide therapeutic benefits against lung cancer. In this study, thirty-four chiral compounds designed by combining benzoxadiazole and sulfonamide moieties on the skeleton of the same molecule have been synthesized in S and R enantiomeric forms. In vitro cytotoxic activity and apoptotic effects of the compounds (1a–17a, 1b–17b) have been evaluated using A549 lung cancer cell line and the compounds that induced apoptosis in A549 cells and reduced mRNA expression levels of HIF-targeted genes have been evaluated. Consequently, four molecules with high potential have been developed as target compounds (4b, 6a, 6b and 7a), and the pharmacokinetic properties of these molecules have been determined theoretically. Also, emerging computational methods such as molecular docking, which are conducted to estimate the modes of the interactions of the compounds with HIF-1β, calculations of binding energy and ADMET analysis, have been applied to support the results of in vitro cytotoxic activity. Taken together with all the results, compound 6a with the R configuration seems to be a promising HIF-1β inhibitor candidate for targeted therapy. [ABSTRACT FROM AUTHOR]

Take Home Message: Capsaicin modified inflammatory response and caused toxicity in bronchial epithelial cultures from patients with COPD. More importantly, capsaicin decreased ciliary beat frequency and induced epithelial permeability and these effects were partially prevented by formoterol and roflumilast.Tear gas is widely used to halt mass demonstrations. Studies have reported its adverse effects on multiple organ systems; however, its effect on individuals with chronic respiratory diseases and the underlying mechanisms of these effects are unclear. For the first time in the literature, we investigated the effects of capsaicin, the active ingredient of tear gas, on bronchial epithelial cell (BEC) cultures obtained from well-characterized groups of nonsmokers, smokers, and patients with chronic obstructive pulmonary disease (COPD). BEC cultures were incubated with 50-500 μM capsaicin in the absence and presence of formoterol (1μM) and roflumilast (0.1 μM) for 24 h. Ciliary beat frequency (CBF) and transepithelial electrical resistance (TEER) were assessed at T1/4, T1/2, T1, T2, T4, T6, and T24 h, whereas the release of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-8, and lactate dehydrogenase (LDH) was measured at T24 h. Capsaicin (250 µM) significantly decreased CBF of all BEC cultures from T1/4 h to T24 h (p