title: CD40 amplifies Fas-mediated apoptosis: a mechanism contributing to emphysema.
abstract: Excessive apoptosis and prolonged inflammation of alveolar cells are associated with the pathogenesis of pulmonary emphysema. We aimed to determine whether CD40 affects alveolar epithelial cells and endothelial cells, with regard to evoking apoptosis and inflammation. Mice were repeatedly treated with agonistic-anti CD40 antibody (Ab), with or without agonistic-anti Fas Ab, and evaluated for apoptosis and inflammation in lungs. Human pulmonary microvascular endothelial cells and alveolar epithelial cells were treated with agonistic anti-CD40 Ab and/or anti-Fas Ab to see their direct effect on apoptosis and secretion of proinflammatory molecules in vitro. Furthermore, plasma soluble CD40 ligand (sCD40L) level was evaluated in patients with chronic obstructive pulmonary disease (COPD). In mice, inhaling agonistic anti-CD40 Ab induced moderate alveolar enlargement. CD40 stimulation, in combination with anti-Fas Ab, induced significant emphysematous changes and increased alveolar cell apoptosis. CD40 stimulation also enhanced IFN-γ-mediated emphysematous changes, not via apoptosis induction, but via inflammation with lymphocyte accumulation. In vitro, Fas-mediated apoptosis was enhanced by CD40 stimulation and IFN-γ in endothelial cells and by CD40 stimulation in epithelial cells. CD40 stimulation induced secretion of CCR5 ligands in endothelial cells, enhanced with IFN-γ. Plasma sCD40L levels were significantly increased in patients with COPD, inversely correlating to the percentage of forced expiratory volume in 1 s and positively correlating to low attenuation area score by CT scan, regardless of smoking history. Collectively CD40 plays a contributing role in the development of pulmonary emphysema by sensitizing Fas-mediated apoptosis in alveolar cells and increasing the secretion of proinflammatory chemokines.
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Shigeta
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tada
authors.forename: Ji-Yang
authors.initials: JY
authors.lastname: Wang
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Ishizaki
authors.forename: Junichi
authors.initials: J
authors.lastname: Tsuyusaki
authors.forename: Keita
authors.initials: K
authors.lastname: Yamauchi
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kasahara
authors.forename: Ken
authors.initials: K
authors.lastname: Iesato
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Tanabe
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Takiguchi
authors.forename: Akemi
authors.initials: A
authors.lastname: Sakamoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tokuhisa
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Shibuya
authors.forename: Kenzo
authors.initials: K
authors.lastname: Hiroshima
authors.forename: James
authors.initials: J
authors.lastname: West
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tatsumi
mesh_terms: D000368:Aged; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis; D019013:CD40 Antigens / Q000819:agonists / Q000276:immunology / Q000378:metabolism*; D023201:CD40 Ligand / Q000097:blood / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000473:pathology; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000378:metabolism; D011656:Pulmonary Emphysema / Q000378:metabolism* / Q000473:pathology; D019713:Receptors, CCR5 / Q000378:metabolism; D019014:fas Receptor / Q000819:agonists / Q000276:immunology / Q000378:metabolism*
chemical_list: D000906:Antibodies; D019013:CD40 Antigens; D019742:Chemokines, CC; C491899:Fas protein, mouse; D019713:Receptors, CCR5; D019014:fas Receptor; D023201:CD40 Ligand; D007371:Interferon-gamma; C505409:Casp3 protein, mouse; D053148:Caspase 3