Docosahexaenoic acid derivative prevents inflammation and hyperreactivity in lung: implication of PKC-Potentiated inhibitory protein for heterotrimeric myosin light chain phosphatase of 17 kD in asthma.
The effects of a newly synthesized docosahexaenoic acid (DHA) derivative, CRBM-0244, on lung inflammation and airway hyperresponsiveness were determined in an in vitro model of TNF-α-stimulated human bronchi and in an in vivo model of allergic asthma. Mechanical tension measurements revealed that CRBM-0244 prevented bronchial hyperresponsiveness in TNF-α-pretreated human bronchi. Moreover, treatment with CRBM-0244 resulted in a decrease in NF-κB activation and cyclooxygenase-2 (COX-2) overexpression triggered by TNF-α. The inhibition of peroxisome proliferator-activated receptor-γ with GW9662 abolished the CRBM-0244-mediated anti-inflammatory effects. CRBM-0244 reduced the Ca(2+) sensitivity of bronchial smooth muscle through a decrease in the phosphorylation and expression of the PKC-potentiated inhibitory protein for heterotrimeric myosin light chain phosphatase of 17 kDa (CPI-17). Results also revealed an overexpression of CPI-17 protein in lung biopsies derived from patients with asthma. Furthermore, the presence of specialized enzymes such as 5-lipoxygenase and 15-lipoxygenase in the lung may convert CRBM-0244 into active mediators, leading to the resolution of inflammation. The in vivo anti-inflammatory properties of CRBM-0244 were also investigated in a guinea pig model of allergic asthma. After oral administration of CRBM-0244, airway leukocyte recruitment, airway mucus, ovalbumin-specific IgE, and proinflammatory markers such as TNF-α and COX-2 were markedly reduced. Hence, CRBM-0244 treatment prevents airway hyperresponsiveness, Ca(2+) hypersensitivity, and the overexpression of CPI-17 in lung tissue. Together, these findings provide key evidence regarding the mode of action of CRBM-0244 in the lung, and point to new therapeutic strategies for modulating inflammation in patients with asthma.
Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Quebec, Canada.
Caroline
C
Morin
Samuel
S
Fortin
André M
AM
Cantin
Eric
E
Rousseau
D000818:Animals; D001249:Asthma / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D015153:Blotting, Western; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002118:Calcium / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000737:chemistry* / Q000494:pharmacology; D005260:Female; D005455:Fluorescent Antibody Technique; D006168:Guinea Pigs; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008175:Lung Neoplasms / Q000473:pathology / Q000601:surgery; D008297:Male; D050178:Monoglycerides / Q000494:pharmacology*; D009124:Muscle Proteins; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D011493:Protein Kinase C / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C561501:CRBM 0244; D047908:Intracellular Signaling Peptides and Proteins; D050178:Monoglycerides; D009124:Muscle Proteins; D016328:NF-kappa B; C107507:PPP1R14A protein, human; D014409:Tumor Necrosis Factor-alpha; D004281:Docosahexaenoic Acids; D051546:Cyclooxygenase 2; D011493:Protein Kinase C; D010749:Phosphoprotein Phosphatases; D002118:Calcium