title: The role of the CCR1 receptor in the inflammatory response to tobacco smoke in a mouse model.
abstract: OBJECTIVE
  The aim was to create pathological changes in mice relevant to human smoke exposure that can be used to further understand the mechanisms and pathology of smoke-induced inflammatory disease.
  
  
  METHODS
  Mice were exposed to tobacco smoke or lipopolysaccharide (LPS) to generate an inflammatory infiltrate within the lungs.
  
  
  RESULTS
  Tobacco smoke exposure over a 4 day period led to neutrophilia in the lungs of BALB/c mice. Within the inflammatory exudates, significant changes were also seen in protein levels of IL-1B, IL-6, MIP-2, KC (IL-8) and TIMP-1 as measured by ELISA. Further protein changes, as measured via multiplex analysis revealed increased levels of MMP-9, MDC, LIF and MCP-1, amongst other mediators. Major changes in whole lung tissue gene expression patterns were observed. The neutrophilia seen after smoke exposure was steroid-insensitive, relative to doses of steroid needed to reduce LPS-driven neutrophilia in controls. This exposes pathological switches that are changed upon exposure to tobacco smoke, rendering steroids less effective under these conditions. Challenge of chemokine receptor type 1 (CCR1) KO mice in the tobacco smoke model showed that lack of this gene protected the mice from smoke-induced inflammation.
  
  
  CONCLUSIONS
  This suggests the CCR1 receptor has a key role in the pathogenesis of smoke-induced inflammation.
authors.affiliation: Integrative Pharmacology, Department of Biosciences, AstraZeneca R&D Lund, Respiratory and Inflammation Research Area, 22187 Lund, Sweden.
authors.forename: Per-Ola
authors.initials: PO
authors.lastname: Onnervik
authors.forename: Maria
authors.initials: M
authors.lastname: Lindahl
authors.forename: Naila
authors.initials: N
authors.lastname: Svitacheva
authors.forename: Martin
authors.initials: M
authors.lastname: Stämpfli
authors.forename: Kerstin
authors.initials: K
authors.lastname: Thim
authors.forename: Amir
authors.initials: A
authors.lastname: Smailagic
authors.forename: Robert
authors.initials: R
authors.lastname: Virtala
authors.forename: John D
authors.initials: JD
authors.lastname: Taylor
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D005260:Female; D015870:Gene Expression; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000188:drug therapy / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D054389:Receptors, CCR1 / Q000235:genetics / Q000378:metabolism*; D012906:Smoke / Q000009:adverse effects*; D013256:Steroids / Q000627:therapeutic use
chemical_list: C515301:Ccr1 protein, mouse; D008070:Lipopolysaccharides; D054389:Receptors, CCR1; D012906:Smoke; D013256:Steroids
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