title: Inhaled KMUP-1 Prevents Allergic Pulmonary Vascular Inflammation and Remodeling via NO and Suppressed MMP-9 and ICAM-1/VCAM-1.
abstract: OBJECTIVE
  This study determines whether KMUP-1 inhalation suppresses ovalbumine (OVA)-sensitized and - challenged peri-bronchial vascular inflammation and remodeling in mice.
  
  
  RESULTS
  After short-term KMUP-1 (1-5 mM, 30 min)-nebulization and L-NAME (12 mM, 15 min)- pretreatment, endothelial nitric oxide synthase (eNOS) and matrix metalloproteinases-9 (MMP-9) expression in lung were measured by Western blotting analysis. In 28-days experiment, mice were sensitized with intraperitoneal OVA on day 1 and day 8, challenged with OVA nebulization and treated with KMUP-1 nebulization (5 mM, 30 mins) on day 21-27. Expression of eNOS, inducible nitric oxide synthase (iNOS), soluble guanylyl cyclase (sGC), protein kinase G (PKG), MMP-9, VCAM-1 and ICAM-1 were measured by Western blotting analysis. eNOS- and MMP-9-immunostaining were used for peri-vascular or peri-bronchial localization. Hematoxylin and eosin staining was used to show the vascular and bronchial wall thickness and infiltration of inflammatory cells. Cell counting and measurement of NOmetabolite (NOx) in bronchoalveolar lavage fluid (BALF) were used to examine the NO production. KMUP-1 increased eNOS and decreased MMP-9 expression. L-NAME-pretreatment reversed these changes. KMUP-1 reduced OVA-sensitized vascular and bronchial wall thickening, eNOS-immunostaining at the alveolar septa, MMP-9-immunostaining in the bronchioles and infiltrated inflammatory cells in the peri-vascular and peri-bronchiolar regions. The OVA-sensitized decrease of sGC and PKG and increase of iNOS, ICAM-1/VCAM-1 and plasma cytokines IL-5/IL-13 were reversed; cell count, NOx and MMP-9-activity in BALF were decreased by KMUP-1.
  
  
  CONCLUSIONS
  Inhaled KMUP-1, preventing allergic pulmonary vascular inflammation and remodeling, would be useful for the treatment of asthma and respiratory obstruction disease.
authors.affiliation: Department of Internal Medicine, Yuan’s General Hospital, Kaohsiung, Taiwan.
authors.forename: Chung-Pin
authors.initials: CP
authors.lastname: Liu
authors.forename: Chung-Han
authors.initials: CH
authors.lastname: Hsieh
authors.forename: Bin-Nan
authors.initials: BN
authors.lastname: Wu
authors.forename: Jwu-Lai
authors.initials: JL
authors.lastname: Yeh
authors.forename: Zen-Kong
authors.initials: ZK
authors.lastname: Dai
authors.forename: Chee-Yin
authors.initials: CY
authors.lastname: Chai
authors.forename: Ing-Jun
authors.initials: IJ
authors.lastname: Chen
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects*; D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D005260:Female; D006162:Guanylate Cyclase / Q000378:metabolism; D006967:Hypersensitivity / Q000188:drug therapy* / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage*; D011014:Pneumonia / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014970:Xanthines / Q000008:administration & dosage*
chemical_list: D010880:Piperidines; D018160:Receptors, Cytoplasmic and Nuclear; D019010:Vascular Cell Adhesion Molecule-1; D014970:Xanthines; D018799:Intercellular Adhesion Molecule-1; C439304:KMUP 1; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; D017869:Cyclic GMP-Dependent Protein Kinases; D020780:Matrix Metalloproteinase 9; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D019331:NG-Nitroarginine Methyl Ester