title: Role of Transient Receptor Potential Vanilloid 4 in Neutrophil Activation and Acute Lung Injury.
abstract: The cation channel transient receptor potential vanilloid (TRPV) 4 is expressed in endothelial and immune cells; however, its role in acute lung injury (ALI) is unclear. The functional relevance of TRPV4 was assessed in vivo, in isolated murine lungs, and in isolated neutrophils. Genetic deficiency of TRPV4 attenuated the functional, histological, and inflammatory hallmarks of acid-induced ALI. Similar protection was obtained with prophylactic administration of the TRPV4 inhibitor, GSK2193874; however, therapeutic administration of the TRPV4 inhibitor, HC-067047, after ALI induction had no beneficial effect. In isolated lungs, platelet-activating factor (PAF) increased vascular permeability in lungs perfused with trpv4(+/+) more than with trpv4(-/-) blood, independent of lung genotype, suggesting a contribution of TRPV4 on blood cells to lung vascular barrier failure. In neutrophils, TRPV4 inhibition or deficiency attenuated the PAF-induced increase in intracellular calcium. PAF induced formation of epoxyeicosatrienoic acids by neutrophils, which, in turn, stimulated TRPV4-dependent Ca(2+) signaling, whereas inhibition of epoxyeicosatrienoic acid formation inhibited the Ca(2+) response to PAF. TRPV4 deficiency prevented neutrophil responses to proinflammatory stimuli, including the formation of reactive oxygen species, neutrophil adhesion, and chemotaxis, putatively due to reduced activation of Rac. In chimeric mice, however, the majority of protective effects in acid-induced ALI were attributable to genetic deficiency of TRPV4 in parenchymal tissue, whereas TRPV4 deficiency in circulating blood cells primarily reduced lung myeloperoxidase activity. Our findings identify TRPV4 as novel regulator of neutrophil activation and suggest contributions of both parenchymal and neutrophilic TRPV4 in the pathophysiology of ALI.
authors.affiliation: 1 Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China.|2 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Yin
authors.affiliation: 3 Institute of Physiology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Michalick
authors.affiliation: 2 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.|4 Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Tang
authors.affiliation: 2 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Arata
authors.initials: A
authors.lastname: Tabuchi
authors.affiliation: 2 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Neil
authors.initials: N
authors.lastname: Goldenberg
authors.affiliation: 2 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Qinghong
authors.initials: Q
authors.lastname: Dan
authors.affiliation: 5 Institute for Vascular Signaling, Center for Molecular Medicine, Goethe University Frankfurt, Frankfurt, Germany.
authors.forename: Khader
authors.initials: K
authors.lastname: Awwad
authors.affiliation: 1 Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China.|2 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Liming
authors.initials: L
authors.lastname: Wang
authors.affiliation: 3 Institute of Physiology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Lasti
authors.initials: L
authors.lastname: Erfinanda
authors.affiliation: 6 Department of Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Nouailles
authors.affiliation: 6 Department of Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Witzenrath
authors.affiliation: 7 Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Alexis
authors.initials: A
authors.lastname: Vogelzang
authors.affiliation: 1 Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Lv
authors.affiliation: 2 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Warren L
authors.initials: WL
authors.lastname: Lee
authors.affiliation: 2 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 2 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.|8 Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ori
authors.initials: O
authors.lastname: Rotstein
authors.affiliation: 2 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.|8 Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Andras
authors.initials: A
authors.lastname: Kapus
authors.affiliation: 2 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.|8 Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Katalin
authors.initials: K
authors.lastname: Szaszi
authors.affiliation: 5 Institute for Vascular Signaling, Center for Molecular Medicine, Goethe University Frankfurt, Frankfurt, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Fleming
authors.affiliation: 9 Department of Medicine/Division of Neurology, Duke Clinics for Pain and Palliative Care, Duke University Medical Center, Durham, North Carolina; and.
authors.forename: Wolfgang B
authors.initials: WB
authors.lastname: Liedtke
authors.affiliation: 10 German Heart Institute Berlin, Berlin, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Kuppe
authors.affiliation: 2 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.|3 Institute of Physiology, Charité Universitätsmedizin Berlin, Berlin, Germany.|8 Department of Surgery, University of Toronto, Toronto, Ontario, Canada.|10 German Heart Institute Berlin, Berlin, Germany.
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Kuebler
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D000818:Animals; D016026:Bone Marrow Transplantation; D020013:Calcium Signaling; D002199:Capillary Permeability; D004195:Disease Models, Animal; D006801:Humans; D006851:Hydrochloric Acid; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D011014:Pneumonia / Q000378:metabolism; D011654:Pulmonary Edema / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C573308:HC-067047; D009025:Morpholines; D011758:Pyrroles; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; C486576:Trpv4 protein, mouse; D006851:Hydrochloric Acid
keywords: acute lung injury; calcium; neutrophil; reactive oxygen sepsis; transient receptor potential vanilloid 4