Involvement of MMP-12 and phosphodiesterase type 4 in cigarette Smoke-induced inflammation in mice

¹ INSERM U620, Faculté de Pharmacie, Université de Rennes 1, Rennes, F-35043, France; and Pfizer Global R&D, Fresnes Laboratories; Fresnes, F-94265 France
² INSERM U620, Faculté de Pharmacie, Université de Rennes 1, Rennes, F-35043, France
³ Pfizer Global R&D, Fresnes Laboratories; Fresnes, F-94265 France; and EliLilly R&D, Indianapolis, US
⁴ Pfizer Global R&D, Fresnes Laboratories; Fresnes, F-94265 France; and Sanofi-Aventis R&D, Paris, France
⁵ Pfizer Global R&D, Fresnes Laboratories; Fresnes, F-94265 France
⁶ Pfizer Global R&D, Fresnes Laboratories; Fresnes, F-94265 France; and AstraZeneca R&D, Loughborough, UK
⁷ Pfizer Global R&D, Fresnes Laboratories; Fresnes, F-94265 France; and AstraZeneca R&D, Alderley Park, Macclesfield, UK

^* To whom correspondence should be addressed. E-mail: vincent.lagente{at}univ-rennes1.fr.

	Abstract

The aims of this study were to characterize a mouse model of airways inflammation induced by cigarette smoke and to compare it with LPS model with regards to the efficacy of a PDE4 inhibitor, cilomilast, and a corticosteroid, dexamethasone and macrophage metalloelastase (MMP-12) gene deletion.

Cigarette smoke exposure for 3 days induced a time-dependent airway neutrophilia associated with an increased level of KC, MIP-2, MIP-1alpha and MMP-9 in the BAL. LPS exposure also induced an increase in the number of neutrophils in BAL. Studies in MMP12-/- mice showed that in contrast to the smoking model, MMP-12 did not have a critical role in LPS-induced inflammation. Both cilomilast and dexamethasone blocked LPS-induced neutrophilia in a dose-dependent manner. Cilomilast inhibited cigarette smoke-induced neutrophilia and MIP-1alpha but only 10 mg·kg^-1 of dexamethasone was effective. Both anti-inflammatory treatments had no effect on the levels of KC and MIP-2 in the BAL.

Although the inflammatory response was very similar in the smoking model and LPS, the pharmacological modulation and the MMP12 gene deletion highlighted the differences in the mechanisms involved. Furthermore, the cigarette smoke model seems to better represent the situation described in COPD patients. These differences underline the importance of using acute smoke exposure model to investigate potential new treatments for COPD.

This article has been cited by other articles:

				J. A. Marwick, G. Caramori, C. S. Stevenson, P. Casolari, E. Jazrawi, P. J. Barnes, K. Ito, I. M. Adcock, P. A. Kirkham, and A. Papi Inhibition of PI3K{delta} Restores Glucocorticoid Function in Smoking-induced Airway Inflammation in Mice Am. J. Respir. Crit. Care Med., April 1, 2009; 179(7): 542 - 548. [Abstract] [Full Text] [PDF]

				A. Morris, G. Kinnear, W.-Y. H. Wan, D. Wyss, P. Bahra, and C. S. Stevenson Comparison of Cigarette Smoke-Induced Acute Inflammation in Multiple Strains of Mice and the Effect of a Matrix Metalloproteinase Inhibitor on These Responses J. Pharmacol. Exp. Ther., December 1, 2008; 327(3): 851 - 862. [Abstract] [Full Text] [PDF]

				R. A. Dean, J. H. Cox, C. L. Bellac, A. Doucet, A. E. Starr, and C. M. Overall Macrophage-specific metalloelastase (MMP-12) truncates and inactivates ELR+ CXC chemokines and generates CCL2, -7, -8, and -13 antagonists: potential role of the macrophage in terminating polymorphonuclear leukocyte influx Blood, October 15, 2008; 112(8): 3455 - 3464. [Abstract] [Full Text] [PDF]

				P. Glader, B. Eldh, S. Bozinovski, K. Andelid, M. Sjostrand, C. Malmhall, G. P. Anderson, G. C. Riise, I. Qvarfordt, and A. Linden Impact of acute exposure to tobacco smoke on gelatinases in the bronchoalveolar space Eur. Respir. J., September 1, 2008; 32(3): 644 - 650. [Abstract] [Full Text] [PDF]

				R. M. Tuder, J. H. Yun, and B. B. Graham Cigarette Smoke Triggers Code Red: p21CIP1/WAF1/SDI1 Switches on Danger Responses in the Lung Am. J. Respir. Cell Mol. Biol., July 1, 2008; 39(1): 1 - 6. [Abstract] [Full Text] [PDF]

				C. L. Quement, I. Guenon, J.-Y. Gillon, V. Lagente, and E. Boichot MMP-12 induces IL-8/CXCL8 secretion through EGFR and ERK1/2 activation in epithelial cells Am J Physiol Lung Cell Mol Physiol, June 1, 2008; 294(6): L1076 - L1084. [Abstract] [Full Text] [PDF]

				S. Medicherla, M. F. Fitzgerald, D. Spicer, P. Woodman, J. Y. Ma, A. M. Kapoun, S. Chakravarty, S. Dugar, A. A. Protter, and L. S. Higgins p38{alpha}-Selective Mitogen-Activated Protein Kinase Inhibitor SD-282 Reduces Inflammation in a Subchronic Model of Tobacco Smoke-Induced Airway Inflammation J. Pharmacol. Exp. Ther., March 1, 2008; 324(3): 921 - 929. [Abstract] [Full Text] [PDF]

				E. Doz, N. Noulin, E. Boichot, I. Guenon, L. Fick, M. Le Bert, V. Lagente, B. Ryffel, B. Schnyder, V. F. J. Quesniaux, et al. Cigarette Smoke-Induced Pulmonary Inflammation Is TLR4/MyD88 and IL-1R1/MyD88 Signaling Dependent J. Immunol., January 15, 2008; 180(2): 1169 - 1178. [Abstract] [Full Text] [PDF]

				T. Yoshida and R. M. Tuder Pathobiology of Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease Physiol Rev, July 1, 2007; 87(3): 1047 - 1082. [Abstract] [Full Text] [PDF]