PMID- 33189900 OWN - NLM STAT- MEDLINE DCOM- 20210917 LR - 20210917 IS - 1522-9629 (Electronic) IS - 1094-5539 (Linking) VI - 64 DP - 2020 Oct TI - Investigating the effect of TRPV4 inhibition on pulmonary-vascular barrier permeability following segmental endotoxin challenge. PG - 101977 LID - S1094-5539(20)30182-6 [pii] LID - 10.1016/j.pupt.2020.101977 [doi] AB - BACKGROUND: Acute Respiratory Distress Syndrome (ARDS) is associated with increased pulmonary-vascular permeability. In the lung, transient receptor potential vanilloid 4 (TRPV4), a Ca(2+)-permeable cation channel, is a regulator of endothelial permeability and pulmonary edema. We performed a Phase I, placebo-controlled, double-blind, randomized, parallel group, proof-of-mechanism study to investigate the effects of TRPV4 channel blocker, GSK2798745, on pulmonary-vascular barrier permeability using a model of lipopolysaccharide (LPS)-induced lung inflammation. METHODS: Healthy participants were randomized 1:1 to receive 2 single doses of GSK2798745 or placebo, 12 h apart. Two hours after the first dose, participants underwent bronchoscopy and segmental LPS instillation. Total protein concentration and neutrophil counts were measured in bronchoalveolar lavage (BAL) samples collected before and 24 h after LPS challenge, as markers of barrier permeability and inflammation, respectively. The primary endpoint was baseline adjusted total protein concentration in BAL at 24 h after LPS challenge. A Bayesian framework was used to estimate the posterior probability of any percentage reduction (GSK2798745 relative to placebo). Safety endpoints included the incidence of adverse events (AEs), vital signs, 12-lead electrocardiogram, clinical laboratory and haematological evaluations, and spirometry. RESULTS: Forty-seven participants were dosed and 45 completed the study (22 on GSK2798745 and 23 on placebo). Overall, GSK2798745 was well tolerated. Small reductions in mean baseline adjusted BAL total protein (~9%) and neutrophils (~7%) in the LPS-challenged segment were observed in the GSK2798745 group compared with the placebo group; however, the reductions did not meet pre-specified success criteria of at least a 95% posterior probability that the percentage reduction in the mean 24-h post LPS BAL total protein level (GSK2798745 relative to placebo) exceeded zero. Median plasma concentrations of GSK2798745 were predicted to inhibit TRPV4 on lung vascular endothelial cells by ~70-85% during the 24 h after LPS challenge; median urea-corrected BAL concentrations of GSK2798745 were 3.0- to 8.7-fold higher than those in plasma. CONCLUSIONS: GSK2798745 did not affect segmental LPS-induced elevation of BAL total protein or neutrophils, despite blood and lung exposures that were predicted to be efficacious. CLINICALTRIALS. GOV IDENTIFIER: NCT03511105. CI - Copyright (c) 2020 Elsevier Ltd. All rights reserved. FAU - Mole, Sarah AU - Mole S AD - GlaxoSmithKline, Gunnells Wood Road, Stevenage, UK. Electronic address: sarah.x.mole@gsk.com. FAU - Harry, Anya AU - Harry A AD - GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA, 19426, USA. FAU - Fowler, Andy AU - Fowler A AD - GlaxoSmithKline, Stockley Park, West Uxbridge, Middlesex, UB11 1BT, UK. FAU - Hotee, Sarah AU - Hotee S AD - GlaxoSmithKline, Gunnells Wood Road, Stevenage, UK. FAU - Warburton, Joseph AU - Warburton J AD - GlaxoSmithKline, Gunnells Wood Road, Stevenage, UK. FAU - Waite, Sarah AU - Waite S AD - GlaxoSmithKline, Stockley Park, West Uxbridge, Middlesex, UB11 1BT, UK. FAU - Beerahee, Misba AU - Beerahee M AD - GlaxoSmithKline, Gunnells Wood Road, Stevenage, UK. FAU - Behm, David J AU - Behm DJ AD - GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA, 19426, USA. FAU - Badorrek, Philipp AU - Badorrek P AD - Fraunhofer-Institut Fuer Toxikologie und Experimentelle Medizin [ITEM], Nikolai-Fuchs-Strasse 1, 30625, Hannover, Germany. FAU - Muller, Meike AU - Muller M AD - Fraunhofer-Institut Fuer Toxikologie und Experimentelle Medizin [ITEM], Nikolai-Fuchs-Strasse 1, 30625, Hannover, Germany. FAU - Faulenbach, Cornelia AU - Faulenbach C AD - Fraunhofer-Institut Fuer Toxikologie und Experimentelle Medizin [ITEM], Nikolai-Fuchs-Strasse 1, 30625, Hannover, Germany. FAU - Lazaar, Aili L AU - Lazaar AL AD - GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA, 19426, USA. FAU - Hohlfeld, Jens M AU - Hohlfeld JM AD - Fraunhofer-Institut Fuer Toxikologie und Experimentelle Medizin [ITEM], Nikolai-Fuchs-Strasse 1, 30625, Hannover, Germany; Hannover Medical School and German Centre for Lung Research, Medizinische Hochschule Hannover OE6876, Carl-Neuberg-Str. 1, 30625, Hannover, Germany. LA - eng SI - ClinicalTrials.gov/NCT03511105 PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20201113 PL - England TA - Pulm Pharmacol Ther JT - Pulmonary pharmacology & therapeutics JID - 9715279 RN - 0 (Benzimidazoles) RN - 0 (Endotoxins) RN - 0 (GSK2798745) RN - 0 (Lipopolysaccharides) RN - 0 (Spiro Compounds) RN - 0 (TRPV Cation Channels) RN - 0 (TRPV4 protein, human) SB - IM MH - Bayes Theorem MH - Benzimidazoles MH - Bronchoalveolar Lavage Fluid MH - *Capillary Permeability MH - Endothelial Cells MH - Endotoxins MH - Humans MH - Lipopolysaccharides MH - Lung MH - Neutrophils MH - Permeability MH - Spiro Compounds MH - *TRPV Cation Channels OTO - NOTNLM OT - Acute respiratory distress syndrome (ARDS) OT - Bronchoalveolar lavage (BAL) OT - GSK2798745 OT - Segmental lipopolysaccharide (LPS) challenge OT - Transient receptor potential vanilloid 4 (TRPV4) OT - Urea-correction EDAT- 2020/11/16 06:00 MHDA- 2021/09/18 06:00 CRDT- 2020/11/15 20:25 PHST- 2020/08/07 00:00 [received] PHST- 2020/10/20 00:00 [revised] PHST- 2020/11/10 00:00 [accepted] PHST- 2020/11/16 06:00 [pubmed] PHST- 2021/09/18 06:00 [medline] PHST- 2020/11/15 20:25 [entrez] AID - S1094-5539(20)30182-6 [pii] AID - 10.1016/j.pupt.2020.101977 [doi] PST - ppublish SO - Pulm Pharmacol Ther. 2020 Oct;64:101977. doi: 10.1016/j.pupt.2020.101977. Epub 2020 Nov 13.