title: Inhalable powder formulation of vasoactive intestinal peptide derivative, [R15,20,21, L17]-VIP-GRR, attenuated neutrophilic airway inflammation in cigarette smoke-exposed rats.
abstract: Cigarette smoke (CS) has been identified as a predominant causative factor for chronic obstructive pulmonary disease (COPD), so CS-exposed rodent model of COPD has drawn considerable interest and attention for fundamental study and drug discovery. In the present study, using experimental COPD model rats, the therapeutic potential of a newly prepared respirable powder (RP) formulation of a long-acting VIP derivative, [Arg(15,20,21), Leu(17)]-VIP-GRR (IK312532), was assessed with a focus on pro-inflammatory biomarkers, morphological and histochemical changes, and infiltrated cells in the respiratory system. CS exposure of rats for 11 days led to the marked infiltration of inflammatory cells, except for eosinophils, in bronchiolar epithelium, followed by goblet cell metaplasia and hyperplasia. However, inhalation of IK312532-RP (50μg/rat) in the CS-exposed rats resulted in 74 and 71% reductions of granulocyte recruitment in bronchoalveolar lavage fluids and lung tissues, respectively, with 68% decrease of goblet cells. Biomarker study demonstrated that the inhaled IK312532-RP could suppress the CS-evoked increase of myeloperoxidase in both plasma and lung by 87 and 70%, respectively, possibly leading to potent suppression of neutrophilic inflammatory symptoms. The results from TUNEL staining were indicative of apoptotic damage in respiratory tissues of the CS-exposed rats, and there appeared to be marked decrease of TUNEL-positive cells in the CS-exposed rat with inhaled IK312532-RP. The present findings suggest that an inhalable formulation of IK312532 might be efficacious as a therapy for COPD or other airway inflammatory diseases because of its potent immunomodulating activities.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka 422-8526, Japan. onoue@u-shizuoka-ken.ac.jp
authors.forename: Satomi
authors.initials: S
authors.lastname: Onoue
authors.forename: Shingen
authors.initials: S
authors.lastname: Misaka
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Aoki
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Karaki
authors.forename: Atsukazu
authors.initials: A
authors.lastname: Kuwahara
authors.forename: Asami
authors.initials: A
authors.lastname: Ohide
authors.forename: Takahiro
authors.initials: T
authors.lastname: Mizumoto
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D015415:Biomarkers; D047209:Eosinophil Peroxidase / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D008171:Lung Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D009195:Peroxidase / Q000378:metabolism; D011208:Powders; D051381:Rats; D017207:Rats, Sprague-Dawley; D020545:Respiratory Mucosa / Q000187:drug effects / Q000473:pathology; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana; D014660:Vasoactive Intestinal Peptide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D011208:Powders; D012906:Smoke; C511374:vasoactive intestinal peptide-GRR, Arg(15,20,21)-Leu(17)-; D014660:Vasoactive Intestinal Peptide; D047209:Eosinophil Peroxidase; D009195:Peroxidase