title: Long-acting analogue of vasoactive intestinal peptide, [R15, 20, 21, L17]-VIP-GRR (IK312532), protects rat alveolar L2 cells from the cytotoxicity of cigarette smoke.
abstract: Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) act as neurotransmitters in numerous biological responses. We previously reported that the replacement of Lys by Arg, and Met by Leu in VIP (IK312532; [Arg15, 20, 21, Leu17]-VIP) resulted in a significant improvement in metabolic stability and biological activity. In the present study, we investigated the effect of VIP and its related peptides including long-acting VIP derivative (IK312532) and PACAP27 on the cytotoxicity of cigarette smoke extract (CSE), a causative factor of chronic obstructive pulmonary disease (COPD), in rat alveolar L2 cells. RT-PCR displayed the dominant expression of mRNA for the VIP-specific VPAC2 receptor in L2 cells, and VIP and the related peptides showed the specific binding activity and potent stimulation of adenylate cyclase. CSE at a concentration of 0.1% or higher induced significant apoptotic death of L2 cells. Interestingly, the addition of neuropeptides at a concentration of 10(-11) M or higher in L2 cells with CSE (0.25%) resulted in significant attenuation of cell death with the deactivation of CSE-evoked caspase-3 activity. IK312532 was much stable against the enzymatic digestion compared to VIP, and the protective effect of IK312532 was 1.6-fold higher than that of VIP. Taken together with our previous report showing that IK312532 has long-acting relaxant activity in the lung, IK312532 may be a potential candidate for drug treatment of asthma and COPD.
authors.affiliation: Health Science Division, Itoham Foods Inc., 1-2-1 Kubogaoka, Moriya, Ibaraki 302-0104, Japan. onoue@fureai.or.jp
authors.forename: Satomi
authors.initials: S
authors.lastname: Onoue
authors.forename: Kosuke
authors.initials: K
authors.lastname: Endo
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ohmori
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
authors.forename: Ryohei
authors.initials: R
authors.lastname: Kimura
authors.forename: Takehiko
authors.initials: T
authors.lastname: Yajima
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Kashimoto
mesh_terms: D000818:Animals; D001249:Asthma / Q000188:drug therapy; D001483:Base Sequence; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D009414:Nerve Growth Factors / Q000494:pharmacology; D009479:Neuropeptides / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018005:Receptors, Vasoactive Intestinal Peptide / Q000235:genetics; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana; D014660:Vasoactive Intestinal Peptide / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C495401:ADCYAP1 protein, human; C495403:Adcyap1 protein, rat; D018076:DNA, Complementary; D009414:Nerve Growth Factors; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D012333:RNA, Messenger; D018005:Receptors, Vasoactive Intestinal Peptide; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D012906:Smoke; D014660:Vasoactive Intestinal Peptide; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases