Role of Transient Receptor Potential Vanilloid 4 in Neutrophil Activation and Acute Lung Injury
| Autor: | Jun Yin, Warren L. Lee, Wolfgang M. Kuebler, Wolfgang Liedtke, Lasti Erfinanda, Christine Tang, Laura Michalick, Arata Tabuchi, Geraldine Nouailles, Alexis Vogelzang, Haibo Zhang, Qinghong Dan, Liming Wang, Hermann Kuppe, Katalin Szászi, Andras Kapus, Lu Lv, Martin Witzenrath, Neil M. Goldenberg, Ingrid Fleming, Ori D. Rotstein, Khader Awwad |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine TRPV4 Male Neutrophils Morpholines Clinical Biochemistry Acute Lung Injury TRPV Cation Channels Vascular permeability Pulmonary Edema Pharmacology Lung injury Epoxyeicosatrienoic acid TRPV Neutrophil Activation Proinflammatory cytokine Capillary Permeability 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Immune system medicine Animals Humans Pyrroles Calcium Signaling Molecular Biology Lung Bone Marrow Transplantation Mice Knockout Cell Biology Pneumonia respiratory system Pulmonary edema medicine.disease respiratory tract diseases Disease Models Animal 030104 developmental biology chemistry 030220 oncology & carcinogenesis Immunology Hydrochloric Acid |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology |
| ISSN: | 1535-4989 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|