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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Comparison of Cigarette Smoke-Induced Acute Inflammation in Multiple Strains of Mice and the Effect of a Matrix Metalloproteinase Inhibitor on These Responses

Respiratory Disease Area, Novartis Institutes for BioMedical Research, Horsham, United Kingdom (C.S.S., A.M., D.W., G.K., W.-Y.H.W., P.B.); and Centre for Integrative Mammalian Physiology and Pharmacology (C.S.S.), Respiratory Pharmacology Group, Airway Disease Section, National Heart and Lung Institute, Imperial College School of Medicine, London, United Kingdom (C.S.S.)

The activities of proteases in the lung, specifically matrix metalloproteinases (MMPs), have been implicated in driving the inflammation and lung destruction observed in smokers with chronic obstructive pulmonary disease. Here, our aims were to compare the acute response with cigarette smoke exposure (CSE) in four mouse strains to identify common and distinguishing features and to assess the effect of an MMP inhibitor on this response. To do this, we exposed mice (BALB/C, C57BL/6, A/J, or 129/Sv) to whole-body CSE (1 h/day) for 3 days. CSE induced dose- and time-dependent increases in neutrophils and keratinocyte chemoattractant levels in the airways of all strains; however, the proportion of the neutrophilia differed among strains. In the two most contrasting strains, BALB/C and C57BL/6, we examined MMP gene expression and found only small changes apart from MMP-12, which was highly expressed in both strains. Both strains were then treated with a broad-spectrum MMP inhibitor, PKF242-484 [(2S,3R)-N⁴-((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-N¹-hydroxy-2-hydroxymethyl-3-(4-methoxy-phenyl)-succinimide] (0.5–10 mg/kg) either orally or intranasally 1 h before and 5 h after CSE for 3 days. PKF242-484 dose-dependently reduced neutrophilia in BALB/C mice when dosed orally (p < 0.01) or intranasally (p < 0.01) but had no clear effect in C57BL/6 by either route. PKF242-484 reduced BAL macrophages when dosed intranasally (p < 0.05) but had no dose-dependent effect when dosed orally in both strains. These data suggest the inflammation induced by CSE is similar, but not identical, in different mouse strains. In addition, the ability of broad-spectrum MMP inhibitors to inhibit smoke-induced acute neutrophil inflammation is strain-dependent, whereas its ability to limit macrophage infiltration may be route dependent.

Address correspondence to: Dr. Christopher S. Stevenson, Respiratory Pharmacology, National Heart and Lung Institute, Sir Alexander Fleming Building, 1st Floor, South Kensington Campus, London SW7 2AZ, United Kingdom. E-mail: c.stevenson{at}imperial.ac.uk

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