Receptor-mediated activation of CFTR via prostaglandin signaling pathways in the airway

Abstract

Cystic fibrosis (CF) is a genetic disease caused by mutations of the gene encoding a cAMP-activated Cl- channel, the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR modulator therapies consist of small-molecule drugs that rescue mutant CFTR. Regimens of single or combinations of CFTR modulators still rely on endogenous levels of cAMP to regulate CFTR activity. We investigated CFTR activation by the natural mediator prostaglandin E2 (PGE2) and lubiprostone and tested the hypothesis that receptor-mediated CFTR activators can be used in combination with currently available CFTR modulators to increase function of mutant CFTR. Primary cultured airway epithelia were assayed in Ussing chambers. Experimental CFTR activators and established CFTR modulators were applied for 24 h and/or acutely and analyzed for their effect on CFTR activity as measured by changes in short-circuit current (ISC). In non-CF airway epithelia, acute application of lubiprostone and PGE2 activated CFTR to levels comparable to forskolin. Pre-treatment (24 h) with antagonists to prostaglandin receptors EP2 and EP4 abolished the ability of lubiprostone to acutely activate CFTR. In F508del homozygous airway epithelia pre-treated with the triple combination of elexacaftor, tezacaftor, and ivacaftor (ELEXA/TEZ/IVA; i.e., Trikafta), acute application of lubiprostone was able to maximally activate CFTR. Prolonged (24 h) co-treatment of F508del homozygous epithelia with ELEXA/TEZ/IVA and lubiprostone increased acute CFTR activation by ~60% compared to treatment with ELEXA/TEZ/IVA alone. This work establishes the feasibility of targeting prostaglandin receptors to activate CFTR on the airway epithelia and demonstrates that co-treatment with lubiprostone can further restore modulator-rescued CFTR.

In Vitro Methods for Measuring the Permeability of Cell Monolayers

“…This experimental technique was applied in a wide array of research areas, including the study on the mechanisms of diarrheal disease in the setting of Salmonella infection and on the regulation of epithelial chloride secretion by the epidermal growth factor receptor [33], and the research on the cytotoxic effect of smoke from polymer combustion on human lungs [32]. For a long time, the Using chamber systems have been the most frequently used for the study of intestinal epithelium [34], but more recent papers describe the research on the airway epithelia, including the targeting of prostaglandin receptors in cystic fibrosis (CF) treatment [35].…”

One Size Does Not Fit All: The Past, Present and Future of Cystic Fibrosis Causal Therapies

“…Lubiprostone, approved for the treatment of chronic constipation [ 73 ], stimulates fluid secretion via activation of the CFTR channel through prostaglandin receptor EP4 mediated modulation of cAMP levels [ 74 ]. Recently, Shaughnessy and colleagues reported enhanced F508del rescue in CF airway epithelia when Trikafta™/Kaftrio™ was combined with lubiprostone [ 75 ]. The dual phosphodiesterase 3 and 4 inhibitor RPL554 (ensifentrine), in clinical development for chronic obstructive pulmonary disease (COPD) and asthma [ 76 ], was shown to activate CFTR with rare class III and IV mutations [ 77 , 78 ] and was tested in a small phase II trial with promising results ([ 79 ] & NCT02919995).…”

Deficiency of long‐chain acyl‐CoA synthetase 4 leads to lipopolysaccharide‐induced mortality in a mouse model of septic shock

“…The CFTR chloride channel is known to be involved in secretory diarrhea 28 and is activated by the PGE 2 and PG receptor agonist lubiprostone 29 . In addition, a previous report suggested that the inhibition of CFTR reduced fluid secretion in infectious secretory diarrheas 30 .…”