Covid-19 in the beginning an epidemic caused by SARS-CoV-2 has turned out to be a life- threatening global pandemic with increased morbidity and mortality. [16]. AQPs are ubiquitous membrane channel proteins involved in small solute and water transport RKI-1447 in response to osmotic gradients. AQPs are known to exist as tetramers while structurally each 30kDa monomer is made up of six bilayer spanning domain (H1-H6), with two helical segment or loop (HB and HE) partially tucked in opposite orientation into the lipid bilayer with their signature NPA (aspargine- proline- alanine) sequence containing motifs [17]. The AQP superfamily constitutes 13 isoforms (AQP0-12) and based upon their structure and functional features it has been divided into three subfamilies: orthodox/classical aquaporins (AQP0, AQP1, AQP2, AQP4, AQP5) that are strictly water permeable, aquaglyceroporins (AQP3, AQP7, AQP9, AQP10) in addition to water, transports glycerol, urea and other small sized non electrolytes and unorthodox/superaquaporins (AQP6, AQP8, AQP11, AQP12) involved in transport of small uncharged solutes [18]. Out of all AQP isoforms four of them namely AQP1, AQP3, AQP4 and AQP5 are localized in lungs and airways (Table 1 ), and their expression pattern here signifies distinct physiological role in pulmonary fluid maintenance. AQP1 the first isoform to be identified in lung, is expressed in microvascular endothelial cells adjacent to airways and alveoli, in microvessels and mesothelial cells of parietal and visceral pleura. Basal epithelial cells of large airways and nasopharynx are known to express AQP3 in their basolateral membrane and also in human small airway epithelia. AQP4 expression is seen at the basolateral membrane of ciliated columnar epithelial cells of trachea, bronchus and nasopharyngeal region. Type I alveolar epithelial cells of distal lung and acinar cells of nasopharyngeal subepithelial gland shows significant expression of AQP5 on their apical membrane [19]. The tissue, cell specific distribution of AQPs along with their functional characterization have gained considerable scientific interest to investigate their involvement in pathological conditions. Table 1 Tissue-cell specific localization of AQPs in lung. (PA) induced lung injury in wild type mice showed decreased AQP5 mRNA and protein expression. When compared with the wild type, AQP5 knock out mice exhibited severe lung injury with increased wet/dry weight ratio and endothelial permeability thereby concluding the fact that deletion of AQP5 aggravated the progression of acute lung injury (ALI) [24]. Studies by Gabazza em et al /em ., explored the relationship between AQP5 and lung fibrosis. Both AQP5 protein and mRNA expression was downregulated in bleomycin induced lung fibrosis condition. Probably this might be due to chronic lung injury by bleomycin and the decrease in expression of AQP5 might have caused a RKI-1447 persistent and chronic pulmonary edema with successive development of lung fibrosis [25].?Experiments with lungs of aged mice showed an altered water transport associated with AQP1 and AQP5 downregulation. The capillary- airway osmotic water transport rate was decreased with RKI-1447 significant reduction in lung water accumulation indicating a slower hydrostatically driven lung edema formation [26]. Type II alveolar epithelial cells exposed to hyperoxic condition showed significant increase in expression levels of AQP1 with increased cell volume. This indicates the enhanced water transport as a compensatory mechanism to improvise bodys internal environment. Furthermore, prolonged exposure to a high oxygen atmosphere might have gradually aggravated the lung damage downregulating AQP1 leading to drinking water transportation dysfunction [27]. Aquaporin modulators in lung swelling and edema: guaranteeing medicines for Covid-19 comorbidity The above- stated medical data unfolds the participation of AQPs implicating their expressional design during pulmonary swelling, fluid clearance and accumulation. Now the conception, whether direct modulation of AQPs or their related signaling pathway by small molecule inhibitors or modulators could palliate the pathological outcomes of inflammation and associated edema needs to be reviewed (Fig. 1 ). Open in a separate windows Fig. 1 An illustration of hypothesis whether aquaporin (AQP) modulation in RKI-1447 lungs could reduce the impact of Covid-19 illness. The cytokine storm effectuated by SARS-CoV-2 sets up a hyperactive immune response with inflammatory mediators at superfluous levels altering AQP expression and associated water movement. Direct modulation of AQPs or their related signaling pathways via small molecule inhibitors other modulators could alleviate pulmonary edema formation and interstitial fluid accumulation thereby diminishing the ill-effects of Covid-19 comorbidity. Mice with LPS induced ALI, when treated with TGN-020 ANGPT2 an AQP4 inhibitor showed significant decrease in levels of proinflammatory cytokines, a less severe alveolar wall collapse with reduced inflammatory infiltrates and improved survival rate. Inhibition of IL-17A by downregulating PI3K/Akt signaling with an upregulated SOCS3 protein expression is speculated to be the reason behind the alleviation of ALI [28]. Similarly AQP4 inhibition.