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Bronchial inflammation induced PKCζ over-expression: involvement in mechanical properties of airway smooth muscle.
Bronchial inflammation induced PKCζ over-expression: involvement in mechanical properties of airway smooth muscle.
- Source :
-
Canadian journal of physiology and pharmacology [Can J Physiol Pharmacol] 2012 Feb; Vol. 90 (2), pp. 261-9. Date of Electronic Publication: 2012 Feb 10. - Publication Year :
- 2012
-
Abstract
- Protein kinase C variants (PKCs) have been involved in the control of airway smooth muscle (ASM) tone, and abnormalities in PKC-dependent signaling have been associated with respiratory diseases such as asthma. In this study, the role of atypical PKCζ in airway hyperresponsiveness was investigated, using an in-vitro model of TNFα-treated human bronchi and an in vivo guinea pig model of chronic asthma. Our results demonstrated that PKCζ-specific inhibition produced a significant increase in isoproterenol sensitivity in TNFα-treated bronchi and ovalbumin (OVA)-sensitized guinea pig bronchi. The role of epoxy-eicosanoids, known to exert anti-inflammatory effects in lung, on PKCζ expression and activity in these models was evaluated. An enhanced PKCζ protein expression was delineated in TNFα-treated bronchi when compared with control (untreated) and epoxy-eicosanoid-treated bronchi. Measurements of Ca(2+) sensitivity, performed in TNFα-treated bronchi, demonstrated that treatment with myristoylated (Myr) PKCζ peptide inhibitor resulted in significant reductions of pCa-induced tension. Epoxy-eicosanoid treatments had similar effects on Ca(2+) sensitivity in TNFα-treated bronchi. In control and epoxy-eicosanoid-treated bronchi, the phosphorylated forms of p38MAPK and CPI-17 were significantly decreased compared with the TNFα-treated bronchi. An enhanced expression of PKCζ was ascertained in our in-vivo model of allergic asthma. Hence an increased Ca(2+) sensitivity could be explained by the phosphorylation of p38-MAPK, which in turn leads to phosphorylation and activation of the CPI-17 regulatory protein. This process was reversed upon treatment with the Myr-PKCζ-peptide inhibitor. The present data provide relevant evidence regarding the role of PKCζ in human and rodent models of airways inflammation.
- Subjects :
- Adrenergic beta-2 Receptor Agonists pharmacology
Animals
Arachidonic Acids metabolism
Asthma chemically induced
Asthma drug therapy
Asthma physiopathology
Biomechanical Phenomena
Bronchi drug effects
Bronchi physiopathology
Bronchial Hyperreactivity chemically induced
Bronchial Hyperreactivity drug therapy
Bronchial Hyperreactivity physiopathology
Bronchodilator Agents pharmacology
Calcium metabolism
Disease Models, Animal
Dose-Response Relationship, Drug
Female
Guinea Pigs
Humans
Intracellular Signaling Peptides and Proteins
Male
Muscle Proteins
Muscle, Smooth drug effects
Muscle, Smooth physiopathology
Ovalbumin
Phosphoprotein Phosphatases metabolism
Phosphorylation
Pneumonia chemically induced
Pneumonia drug therapy
Pneumonia physiopathology
Protein Kinase C antagonists & inhibitors
Protein Kinase Inhibitors pharmacology
Tissue Culture Techniques
Tumor Necrosis Factor-alpha metabolism
Up-Regulation
p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
p38 Mitogen-Activated Protein Kinases metabolism
Asthma enzymology
Bronchi enzymology
Bronchial Hyperreactivity enzymology
Muscle Contraction drug effects
Muscle Relaxation drug effects
Muscle, Smooth enzymology
Pneumonia enzymology
Protein Kinase C metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1205-7541
- Volume :
- 90
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Canadian journal of physiology and pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 22324796
- Full Text :
- https://doi.org/10.1139/y11-117