Role of CXCR2 in cigarette smoke-induced lung inflammation.
It has been hypothesized that the destruction of lung tissue observed in smokers with chronic obstructive pulmonary disease and emphysema is mediated by neutrophils recruited to the lungs by smoke exposure. This study investigated the role of the chemokine receptor CXCR2 in mediating neutrophilic inflammation in the lungs of mice acutely exposed to cigarette smoke. Exposure to dilute mainstream cigarette smoke for 1 h, twice per day for 3 days, induced acute inflammation in the lungs of C57BL/6 mice, with increased neutrophils and the neutrophil chemotactic CXC chemokines macrophage inflammatory protein (MIP)-2 and KC. Treatment with SCH-N, an orally active small molecule inhibitor of CXCR2, reduced the influx of neutrophils into the bronchoalveolar lavage (BAL) fluid. Histological changes were seen, with drug treatment reducing perivascular inflammation and the number of tissue neutrophils. beta-Glucuronidase activity was reduced in the BAL fluid of mice treated with SCH-N, indicating that the reduction in neutrophils was associated with a reduction in tissue damaging enzymes. Interestingly, whereas MIP-2 and KC were significantly elevated in the BAL fluid of smoke exposed mice, they were further elevated in mice exposed to smoke and treated with drug. The increase in MIP-2 and KC with drug treatment may be due to the decrease in lung neutrophils that either are not present to bind these chemokines or fail to provide a feedback signal to other cells producing these chemokines. Overall, these results demonstrate that inhibiting CXCR2 reduces neutrophilic inflammation and associated lung tissue damage due to acute cigarette smoke exposure.
Thatcher
T H
TH
Department of Medicine, Univ. of Rochester School of Medicine and Dentistry, Lung Biology and Disease Program, 601 Elmwood Ave., Box 850, Rochester, NY 14642, USA.
McHugh
N A
NA
Egan
R W
RW
Chapman
R W
RW
Hey
J A
JA
Turner
C K
CK
Redonnet
M R
MR
Seweryniak
K E
KE
Sime
P J
PJ
Phipps
R P
RP
D000208:Acute Disease; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D054426:Chemokine CXCL2; D005260:Female; D005966:Glucuronidase / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D015846:Monokines / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana / Q000633:toxicity*
D054426:Chemokine CXCL2; D015846:Monokines; D023063:Receptors, Interleukin-8B; D012906:Smoke; D005966:Glucuronidase