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Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with a very poor prognosis as it has a 2.5 to 5 years mean survival after proper diagnosis. Even nintedanib and pirfenidone cannot halt the progression, though they slow the progression of IPF. Hence, there is a need to understand the novel pathophysiology. Phospholipase A2 (PLA2) could be the ideal candidate to study in IPF, as they have a role in both inflammation and fibrosis. In the present study, we have shown the expression profile of various secretory Phospholipase A2 (PLA2) isoforms by analyzing publicly available transcriptome data of single cells from the lungs of healthy individuals and IPF patients. Among 11 members of sPLA2, PLA2G2A is found to be increased in the fibroblasts and mesothelial cells while PLA2G5 is found to be increased in the fibroblasts of IPF patients. We identified a subset of fibroblasts expressing high PLA2G2A with moderate expression of PLA2G5 and which are specific to IPF only; we named...

The features of allergic asthma are believed to be mediated mostly through the Th2 immune response. In this Th2-dominant concept, the airway epithelium is presented as the helpless victim of Th2 cytokines. However, this Th2-dominant concept is inadequate to fill some of the vital knowledge gaps in asthma pathogenesis, like the poor correlation between airway inflammation and airway remodeling and severe asthma endotypes, including Th2-low asthma, therapy resistance, etc. Since the discovery of type 2 innate lymphoid cells in 2010, asthma researchers started believing in that the airway epithelium played a crucial role, as alarmins, which are the inducers of ILC2, are almost exclusively secreted by the airway epithelium. This underscores the eminence of airway epithelium in asthma pathogenesis. However, the airway epithelium has a bipartite functionality in sustaining healthy lung homeostasis and asthmatic lungs. On the one hand, the airway epithelium maintains lung homeostasis again...

The ‘era of corticosteroids’ brought about a revolutionary change in the course of asthma treatment in the mid-twentieth century. A few decades later, a lack of response to corticosteroids was recognised in some asthma patients, thereby revealing a distinct endotype of the disease called ‘steroid-resistant asthma’. This finding set in motion a plethora of research to elucidate its inducers and unravel the underlying mechanisms driving this variant. Surprisingly, apart from possible genetic factors and infection, lifestyle-related conditions like stress and obesity were found to invoke this disease. Alteration in the pathways mediating anti-inflammatory effect of glucocorticoids, defective autophagy, certain immune mediators and micro RNAs has been found to slacken the steroid response in asthma. This chapter focuses on the fundamental cell types and key mechanistic pathways involved in steroid-resistant asthma and also discusses the treatment strategies that have been adopted to com...

Many a times, a very thin line exists between physiology and pathology. Airway obstruction seen in the asthmatic subjects is exemplary of such phenomena. Physiologically, airway obstruction is needed to guard the master regulator of lung homeostasis, i.e. the alveolar epithelial cells, against the massive entry of exogenous irritants like noxious particles, allergens and microbes into the airway. Surprisingly, genetic predisposition with prolonged exposure to these exogenous irritants sets off the pathological clock causing mild-moderate- severe asthma. With time, numerous innate and adaptive immune cell types along with cytokines have been pinpointed which participates in the pathogenesis of asthma. Though Th2 cytokines form the foundation of the majority of the asthmatic situation, researchers started dividing the patients as Th2-high and Th2-low asthma. The recent concept of classifying asthma based on its endotypes is a more granular approach to avert the progression of asthma r...

Asthmatics with poor steroid responsiveness are now found to use health services at higher frequency and contribute to socio-economic burden disproportionately. We have previously shown that a ω-6 fatty acid metabolite leads to a severe and steroid insensitive asthma-like condition in mice. Here, we investigated the role of retinoid-x-receptor gamma (RXRγ) and Docosahexaenoic acid (DHA), a ω3 fatty acid rexinoid ligand of RXR, on the features of steroid insensitivity in asthmatic condition. RXRγ was found to be reduced in the lungs of human asthmatics and mice with steroid insensitive allergic airway inflammation. RXRγ knockdown in naïve mice led to spontaneous asthma like features whereas RXRγ knockdown in allergic mice led to steroid insensitive asthma features. We observed while RXRγ binds to the glucocorticoid receptor (GR) gene and regulates its transcription, DHA increases the GRα expression in human bronchial epithelial cells and reverses the steroid insensitive features in m...