Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide attenuate the cigarette smoke extract-induced apoptotic death of rat alveolar L2 cells.
Chronic obstructive pulmonary disease is a major clinical disorder usually associated with cigarette smoking. A central feature of chronic obstructive pulmonary disease is inflammation coexisting with an abnormal protease/antiprotease balance, leading to apoptosis and elastolysis. In an in vitro study of rat lung alveolar L2 cells, cigarette smoke extract (CSE) induced apoptotic cell death. Exposure of L2 cells to CSE at a concentration of 0.25% resulted in a 50% increase of caspase-3 and matrix metalloproteinase (MMP) activities. Specific inhibitors for caspases and MMPs attenuated the cytotoxicity of CSE. RT-PCR amplification identified VPAC2 receptors in L2 cells. A radioligand-binding assay with (125)I-labeled vasoactive intestinal peptide (VIP) found high affinity and saturable (125)I-labeled VIP-binding sites in L2 cells. VIP and pituitary adenylate cyclase-activating polypeptide (PACAP27) were approximately equipotent for both VIP receptor binding and stimulation of cAMP production in L2 cells. Both neuropeptides, at concentrations higher than 10(-13) m, produced a concentration-dependent inhibition of CSE-induced cell death in L2 cells. VIP, at 10(-7) m, reduced CSE-stimulated MMP activity and caspase-3 activation. The present study has shown that VIP and PACAP27 significantly attenuate the cytotoxicity of CSE through the activation of VPAC2 receptor, and the protective effect of VIP may partly be the result of a reduction in the CSE-induced stimulation of MMPs and caspases.
Onoue
Satomi
S
Health Science Division, Itoham Foods Inc., Moriya, Ibaraki, Japan. onoue@fureai.or.jp
Ohmori
Yuki
Y
Endo
Kosuke
K
Yamada
Shizuo
S
Kimura
Ryohei
R
Yajima
Takehiko
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009479:Neuropeptides / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology; D051381:Rats; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D011979:Receptors, Pituitary Hormone / Q000032:analysis; D018005:Receptors, Vasoactive Intestinal Peptide / Q000032:analysis; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*
C495403:Adcyap1 protein, rat; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D011979:Receptors, Pituitary Hormone; D018005:Receptors, Vasoactive Intestinal Peptide; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D012906:Smoke; C495511:Vipr2 protein, rat; D014660:Vasoactive Intestinal Peptide; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D020782:Matrix Metalloproteinases