The role of the CCR1 receptor in the inflammatory response to tobacco smoke in a mouse model.
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.
Onnervik
Per-Ola
PO
Integrative Pharmacology, Department of Biosciences, AstraZeneca R&D Lund, Respiratory and Inflammation Research Area, 22187 Lund, Sweden.
Lindahl
Maria
M
Svitacheva
Naila
N
Stämpfli
Martin
M
Thim
Kerstin
K
Smailagic
Amir
A
Virtala
Robert
R
Taylor
John D
JD
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
C515301:Ccr1 protein, mouse; D008070:Lipopolysaccharides; D054389:Receptors, CCR1; D012906:Smoke; D013256:Steroids
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