Loss of CFTR causes endothelial barrier failure in pneumonia via inhibition of WNK1 and TRPV4 activation

Role of pirfenidone in TGF-β pathways and other inflammatory pathways in acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a theoretical perspective

“…More literature evidence regarding the relationship between CFTR and endothelial cells support this fact. Erfinanda et al found that CFTR downregulation causes increased permeability of endothelial cells as well as enhanced permeability to chloride and calcium ions through deactivation of WNK lysine deficient protein kinase 1(WNK 1) and activation of transient receptor potential cation channel subfamily V member 4 (TRPV4) [62]. WNK1 acts as a regulatory factor for several ion channels and exerts an inhibitory effect on TRPV4 via decreased surface expression [63].…”

Investigating the effect of TRPV4 inhibition on pulmonary-vascular barrier permeability following segmental endotoxin challenge

“…A recent study indicates that TRPV4 expressed on macrophages may protect the lung against bacterial (Pseudomonas aeruginosa) infectionassociated lung tissue injury by enhancing bacterial clearance and reducing proinflammatory cytokine release [Scheraga, 2020]. However, those data contrast with the majority of published pre-clinical data, including results from a similar study where TRPV4 −/− mice were protected against lung edema and protein leak caused by bacterial (Streptococcus pneumoniae) infection [Erfinanda, 2017]. In addition, in our study, we found no evidence to suggest that inhibiting TRPV4 caused increases in barrier permeability or inflammatory markers.…”

Role of innate immunity and systemic inflammation in cystic fibrosis disease progression

“…In addition to Cl − , CFTR also conducts other small anions, like , as well as reactive oxygen species (singlet oxygen) [ 5 ]. It is responsible for the maintenance of intracellular and lysosomal pH, endomembrane reorganization, cell volume, intracellular calcium and redox status, extracellular environment by regulating aquaporins, ceramide metabolism, Toll-like receptor 4 (TLR4) signaling, tight junctions, and ion channels like epithelial sodium channel (ENaC) and transient receptor potential vanilloid type 4 channel (TRPV4) [ 6 , 4 , [7] , [8] , [9] ]. Quantitative loss of CFTR activity underlies CF pathogenesis due to reduced conductance and thereby significant build-up of intracellular Cl − and levels.…”

“…On the plasma membrane, as mentioned before, CFTR regulates the conductance of Cl − and other small anions across the membrane to maintain ionic and water balance both within the cell and in the extracellular apical surface. The absence of normal CFTR function leads to perturbations in basic cellular processes, such as mucus secretion, ciliary movement, cellular integrity, autophagy, cellular metabolism, oxidative burst, protein chlorination, pathogen clearance, endotoxin tolerance, and cell death among others [ 6 , 10 , 11 , 25 ] ( Fig. 2 A).…”

“…Also, the abundantly released ROS even with impaired cellular oxidative burst potentially remodels thickened mucus into a more condensed form by means of aberrant disulphide bridges between cysteine residues of mucins [ 53 , 54 ]. All of this leads to microbial colony establishment and biofilm formation usually due to Pseudomonas aeruginosa and non-typical Hemophilus influenza in the lungs of mice and humans [ 6 , 52 ]. Furthermore, thickened mucus and biofilm together could effectively shield bacteria from NETs, leukocyte attack, and other antibacterial factors like complements and immunoglobins since their movement inside the mucus is restricted due to increased viscosity and loss of fluidity [ 55 ].…”