Transient Receptor Potential Vanilloid 4–Mediated Disruption of the Alveolar Septal Barrier

Abstract

Disruption of the alveolar septal barrier leads to acute lung injury, patchy alveolar flooding, and hypoxemia. Although calcium entry into endothelial cells is critical for loss of barrier integrity, the cation channels involved in this process have not been identified. We hypothesized that activation of the vanilloid transient receptor potential channel TRPV4 disrupts the alveolar septal barrier. Expression of TRPV4 was confirmed via immunohistochemistry in the alveolar septal wall in human, rat, and mouse lung. In isolated rat lung, the TRPV4 activators 4alpha-phorbol-12,13-didecanoate and 5,6- or 14,15-epoxyeicosatrienoic acid, as well as thapsigargin, a known activator of calcium entry via store-operated channels, all increased lung endothelial permeability as assessed by measurement of the filtration coefficient, in a dose- and calcium-entry dependent manner. The TRPV antagonist ruthenium red blocked the permeability response to the TRPV4 agonists, but not to thapsigargin. Light and electron microscopy of rat and mouse lung revealed that TRPV4 agonists preferentially produced blebs or breaks in the endothelial and epithelial layers of the alveolar septal wall, whereas thapsigargin disrupted interendothelial junctions in extraalveolar vessels. The permeability response to 4alpha-phorbol-12,13-didecanoate was absent in TRPV4(-/-) mice, whereas the response to thapsigargin remained unchanged. Collectively, these findings implicate TRPV4 in disruption of the alveolar septal barrier and suggest its participation in the pathogenesis of acute lung injury.

The TRPV4 Channel Contributes to Intercellular Junction Formation in Keratinocytes

“…Another report (58) demonstrated that 4␣-PDD increased lung endothelial permeability, which was blocked by RR. The effect of TRPV4 on barrier functions observed in those reports contradicts that obtained in our own study.…”

Update on vascular endothelial Ca2+signalling: A tale of ion channels, pumps and transporters

“…TRPC3-and TRPC6-induced Ca 2+ inflow underpin the stimulatory effect of VEGF on endothelial proliferation, migration and permeability [18,231,236] , while ATP exploits TRPC3 to activate NF-κB and increase vascular cell adhesion molecule-1 expression [237] . TRPC3-driven NO synthesis and vasore- TRPV1 TRPV2 TRPV3 TRPV4 TRPV5 TRPV6 PCa/PNa and conductance (pS) [202] 10, 35-80 1-3, NM 12, 172 6, 90 > 100, 75 > 100, 40-70 Human coronary artery ECs [300] (+RT-PCR, WB, IHC) Human pulmonary artery ECs [415] +(RT-PCR) +(RT-PCR) +(RT-PCR) Human pulmonary microvascular ECs +(RT-PCR) Human cerebral microvascular ECs [272] +(RT-PCR, IC) Human cerebral arterioles ECs [305] +(RT-PCR, IHC) Human dermal microvascular ECs [319] +(RT-PCR, WB) Breast cancer derived microvascular ECs [319] +(RT-PCR, WB) Human umbilical vein ECs [227,277,296,301] +(RT-PCR) +(WB, IHC) Mouse aortic ECs [280,285,299,306] +(WB) +(RT-PCR, WB, NM, IHC) Mouse pulmonary artery ECs [313] +(WB, IHC) Mouse mesenteric artery ECs [27,280,302] +(RT-PCR, WB, IC) +(RT-PCR, IC) Mouse cerebral microvascular ECs +(RT-PCR) +(RT-PCR, WB) +(RT-PCR) Mouse dermal microvascular ECs [307] +(RT-PCR, WB) Mouse carotid artery ECs [290,296] +(IHC) Rat mesenteric artery ECs [226,275,302] +(WB) +(WB, IC, IHC) Rat femoral artery ECs [312] +(RT-PCR, IC) Rat pulmonary artery ECs [303] +(WB, IHC) Rat renal artery ECs [303] +(IHC) Rat cardiac microvascular ECs [303,…”

Loss of Function of Transient Receptor Potential Vanilloid 1 (TRPV1) Genetic Variant Is Associated with Lower Risk of Active Childhood Asthma

“…TRPV1 activity has been related to different aspects of chronic respiratory disease such as neurogenic inflammation (15,16), irritant-induced chronic cough (13,14), and airway hypersensitivity (17). TRPV4 activation disrupts alveolar barrier in animal models (18) and has been associated with chronic obstructive pulmonary disease in humans (19). Together, these evidences make TRPV1 and TRPV4 interesting candidate genes for asthma.…”