title: Olprinone and colforsin daropate alleviate septic lung inflammation and apoptosis through CREB-independent activation of the Akt pathway.
abstract: Olprinone, a specific phosphodiesterase III inhibitor, and corforsin daropate, a direct adenylate cyclase activator, are now being used in critical conditions. We investigated whether their therapeutic use provides protection against septic acute lung injury (ALI) and mortality. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in BALB/c mice. Olprinone or colforsin daropate was continuously given through an osmotic pump that was implanted into the peritoneal cavity immediately following CLP. These treatments prevented the ALI development in CLP mice, as indicated by the findings that severe hypoxemia, increased pulmonary vascular permeability, and histological lung damage were strikingly remedied. Furthermore, continued administration of olprinone or colforsin daropate suppressed apoptosis induction in septic lungs and improved the survival of CLP mice. Olprinone and corforsin daropate enhanced Akt phosphorylation in septic lungs. Wortmannin, which inhibits the Akt upstream regulator phosphatidylinositol 3-kinase, abrogated the protective effects of olprinone and corforsin daropate on sepsis-associated lung inflammation and apoptosis. In vivo transfection of cyclic AMP response element binding protein (CREB) decoy oligodeoxynucleotide failed to negate the abilities of these agents to increase Akt phosphorylation and to inhibit IκBα degradation in septic lungs. These results demonstrate for the first time that CREB-independent Akt-mediated signaling is a critical mechanism contributing to the therapeutic effects of olprinone and corforsin daropate on septic ALI. Moreover, our data also suggest that these cyclic AMP-related agents, by blocking both nuclear factor-κB activation and apoptosis induction, may represent an effective therapeutic approach to the treatment of the septic syndrome.
authors.affiliation: Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Oishi
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Takano
authors.forename: Kengo
authors.initials: K
authors.lastname: Tomita
authors.forename: Mariko
authors.initials: M
authors.lastname: Takebe
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yokoo
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Yamazaki
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hattori
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002432:Cecum / Q000382:microbiology / Q000473:pathology; D005576:Colforsin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology / Q000627:therapeutic use; D007022:Hypotension / Q000382:microbiology; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008026:Ligation; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011014:Pneumonia / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011728:Pyridones / Q000494:pharmacology* / Q000627:therapeutic use; D012772:Shock, Septic / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D015398:Signal Transduction; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D005576:Colforsin; D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D020536:Enzyme Activators; D007093:Imidazoles; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D010726:Phosphodiesterase Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011728:Pyridones; D000077191:Wortmannin; C492004:Creb1 protein, mouse; C122001:colforsin daropate; C059498:olprinone