title: TRPV4 channels augment macrophage activation and ventilator-induced lung injury.
abstract: We have previously implicated transient receptor potential vanilloid 4 (TRPV4) channels and alveolar macrophages in initiating the permeability increase in response to high peak inflation pressure (PIP) ventilation. Alveolar macrophages were harvested from TRPV4(-/-) and TRPV4(+/+) mice and instilled in the lungs of mice of the opposite genotype. Filtration coefficients (K(f)) measured in isolated perfused lungs after ventilation with successive 30-min periods of 9, 25, and 35 cmH(2)O PIP did not significantly increase in lungs from TRPV4(-/-) mice but increased >2.2-fold in TRPV4(+/+) lungs, TRPV4(+/+) lungs instilled with TRPV4(-/-) macrophages, and TRPV4(-/-) lungs instilled with TRPV4(+/+) macrophages after ventilation with 35 cmH(2)O PIP. Activation of TRPV4 with 4-alpha-phorbol didecanoate (4alphaPDD) significantly increased intracellular calcium, superoxide, and nitric oxide production in TRPV4(+/+) macrophages but not TRPV4(-/-) macrophages. Cross-sectional areas increased nearly 3-fold in TRPV4(+/+) macrophages compared with TRPV4(-/-) macrophages after 4alphaPDD. Immunohistochemistry staining of lung tissue for nitrotyrosine revealed increased amounts in high PIP ventilated TRPV4(+/+) lungs compared with low PIP ventilated TRPV4(+/+) or high PIP ventilated TRPV4(-/-) lungs. Thus TRPV4(+/+) macrophages restored susceptibility of TRPV4(-/-) lungs to mechanical injury. A TRPV4 agonist increased intracellular calcium and reactive oxygen and nitrogen species in harvested TRPV4(+/+) macrophages but not TRPV4(-/-) macrophages. K(f) increases correlated with tissue nitrotyrosine, a marker of peroxynitrite production.
authors.affiliation: Department of Physiology, University of South Alabama, Mobile, Alabama 36688, USA.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Hamanaka
authors.forename: Ming-Yuan
authors.initials: MY
authors.lastname: Jian
authors.forename: Mary I
authors.initials: MI
authors.lastname: Townsley
authors.forename: Judy A
authors.initials: JA
authors.lastname: King
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Liedtke
authors.forename: David S
authors.initials: DS
authors.lastname: Weber
authors.forename: Fabien G
authors.initials: FG
authors.lastname: Eyal
authors.forename: Mary M
authors.initials: MM
authors.lastname: Clapp
authors.forename: James C
authors.initials: JC
authors.lastname: Parker
mesh_terms: D000818:Animals; D004198:Disease Susceptibility; D005838:Genotype; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D008168:Lung / Q000378:metabolism; D008262:Macrophage Activation; D016676:Macrophages, Alveolar / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D051379:Mice; D018345:Mice, Knockout; D010539:Permeability; D010703:Phorbol Esters / Q000494:pharmacology; D011654:Pulmonary Edema / Q000503:physiopathology; D012123:Pulmonary Ventilation; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013194:Staining and Labeling; D050052:TRPC Cation Channels / Q000819:agonists / Q000172:deficiency / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D055397:Ventilator-Induced Lung Injury / Q000473:pathology / Q000503:physiopathology*
chemical_list: D010703:Phorbol Esters; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D050052:TRPC Cation Channels; C489571:TRPC4 ion channel; C002744:3-nitrotyrosine; D014443:Tyrosine; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)