Production and effects of alpha-melanocyte-stimulating hormone during acute lung injury.
Alpha-melanocyte-stimulating hormone (alpha-MSH) is a peptide with broad anti-inflammatory effects. The present research was designed to determine production and effects of alpha-MSH in acute bleomycin-induced lung injury in rats. Intratracheal bleomycin instillation induced alpha-MSH expression in lung infiltrating cells and a marked peptide increase in the circulation. In experiments on the therapeutic potential of alpha-MSH on lung injury, we determined influences of the synthetic alpha-MSH analogue [Nle4-dPhe7]-alpha-MSH (NDP-alpha-MSH) on pulmonary edema, circulating nitric oxide, and gene expression profile in lungs 8 and 24 h after bleomycin instillation. Three main gene categories, known to be involved in the development of acute lung injury, were explored: stress response, inflammation, and fluid homeostasis. Peptide treatment was associated with a significant reduction in interstitial edema, with a virtually normal wet/dry weight ratio. Several stress-related genes, which were either upregulated or reduced by bleomycin, were only marginally altered during NDP-alpha-MSH treatment. NDP-alpha-MSH prevented bleomycin-related transcriptional alterations in genes involved in lung fluid homeostasis, including upregulation of Na/K-transporting ATPase and epithelial sodium channels and downregulation of cystic fibrosis transmembrane conductance regulator. Bleomycin-induced expression of proinflammatory and profibrotic factors (interleukin 6, tumor necrosis factor-alpha, transforming growth factor-beta1, and inducible nitric oxide synthase) and chemokines (chemokine [C-C motif] ligand 2 and chemokine [C-C motif] ligand 5) was likewise significantly reduced by NDP-alpha-MSH. In conclusion, treatment with the alpha-MSH analogue NDP-alpha-MSH greatly improved the clinical and molecular picture of bleomycin-induced lung injury. Treatment with alpha-MSH-related agents can exert beneficial effects in acute lung injury.
Colombo
Gualtiero
G
Center for Preclinical Investigation, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Maggiore Policlinico, Mangiagalli, e Regina Elena, Milano, Italy.
Gatti
Stefano
S
Sordi
Andrea
A
Turcatti
Flavia
F
Carlin
Andrea
A
Rossi
Claudia
C
Lonati
Caterina
C
Catania
Anna
A
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D007249:Inflammation; D008168:Lung / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury; D008297:Male; D008954:Models, Biological; D009569:Nitric Oxide / Q000737:chemistry / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000521:alpha-MSH / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D001761:Bleomycin; D009569:Nitric Oxide; D000521:alpha-MSH; D052247:Nitric Oxide Synthase Type II