title: A combination of secondhand cigarette smoke and Chlamydia pneumoniae accelerates atherosclerosis.
abstract: OBJECTIVE
  Secondhand smoke (SS) induces chronic infection of endothelial cells by Chlamydia pneumoniae (Cpn) in vitro. We investigated the in vivo effect on atherosclerosis following exposure to SS and infection with Cpn both independently and in combination in ApoE-/- mice.
  
  
  RESULTS
  Plaques were largest in the combined SS+Cpn-exposed mice with 12-57% greater cross-sectional area compared with all other groups (P<0.03). Quantitative RT-PCR (qRT-PCR) from aortic roots revealed a synergistic upregulation of both OX40L (CD134L) and MyD88 in SS+Cpn mice (P<0.05). This upregulation occurred despite decreased numbers of macrophage, dendritic cell, CD4 T cell and smooth-muscle-cell infiltrates as determined by quantitative IHC and qRT-PCR. To elucidate whether enhanced apoptosis correlated with reduced plaque cellularity, area of Tdt-mediated dUTP nick labeling positive (TUNEL+) cells and expression of key bridging molecules necessary for efferocytosis (Mertk, Tgm2, FasL and C1qa) were examined. In SS+Cpn mice, there was an increase of the area of TUNEL+ cells in plaque cores (P<0.001) and a downregulation of efferocytosis gene expression (P<0.05). Systemic expression of cytokines in sera (Luminex) showed no differences between groups, suggesting that focal disease mechanisms within the plaque predominated.
  
  
  CONCLUSIONS
  The combination of SS exposure and Cpn infection enhanced atherosclerosis more than either variable did independently by activating inflammatory cells and by promoting growth and maturation of lesions via defective phagocytic clearance and accumulation of apoptotic cells.
authors.affiliation: University of California Davis (UCD) Health System, Pediatrics, 2516 Stockton Blvd, Sacramento, CA 95817, USA. xzhao@hsph.harvard.edu
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhao
authors.forename: De-xiu
authors.initials: DX
authors.lastname: Bu
authors.forename: Kweku
authors.initials: K
authors.lastname: Hayfron
authors.forename: Kent E
authors.initials: KE
authors.lastname: Pinkerton
authors.forename: Charles L
authors.initials: CL
authors.lastname: Bevins
authors.forename: Andrew
authors.initials: A
authors.lastname: Lichtman
authors.forename: Jean
authors.initials: J
authors.lastname: Wiedeman
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000276:immunology*; D023521:Chlamydophila Infections / Q000276:immunology*; D016993:Chlamydophila pneumoniae / Q000276:immunology; D005260:Female; D020287:In Situ Nick-End Labeling; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D053278:OX40 Ligand; D010587:Phagocytosis / Q000276:immunology; D014028:Tobacco Smoke Pollution; D048069:Tumor Necrosis Factors / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D053278:OX40 Ligand; C504586:Tnfsf4 protein, mouse; D014028:Tobacco Smoke Pollution; D048069:Tumor Necrosis Factors