| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Plays a Critical Role in the Pathogenesis of Cigarette Smoke-Induced Pulmonary Emphysema and Inflammation1
,
* Section of Pulmonary and Critical Care Medicine,
Department of Pathology, and
Department of Surgery, Yale University School of Medicine, New Haven, CT 06520;
Department of Pathology and Laboratory Medicine Service, Veterans Administration-Connecticut Health Care System, West Haven, CT 06516; and
¶ Division of Pulmonary Medicine, Department of Internal Medicine, Hanyang University Hospital, College of Medicine, Seoul, Korea
Th1 inflammation and remodeling characterized by local tissue destruction coexist in pulmonary emphysema and other diseases. To test the hypothesis that IL-18 plays an important role in these responses, we characterized the regulation of IL-18 in lungs from cigarette smoke (CS) and room air-exposed mice and characterized the effects of CS in wild-type mice and mice with null mutations of IL-18R
(IL-18R–/–). CS was a potent stimulator and activator of IL-18 and caspases 1 and 11. In addition, although CS caused inflammation and emphysema in wild-type mice, both of these responses were significantly decreased in IL-18R–/– animals. CS also induced epithelial apoptosis, activated effector caspases and stimulated proteases and chemokines via IL-18R-dependent pathways. Importantly, the levels of IL-18 and its targets, cathepsins S and B, were increased in pulmonary macrophages from smokers and patients with chronic obstructive lung disease. Elevated levels of circulating IL-18 were also seen in patients with chronic obstructive lung disease. These studies demonstrate that IL-18 and the IL-18 pathway are activated in CS-exposed mice and man. They also demonstrate, in a murine modeling system, that IL-18R signaling plays a critical role in the pathogenesis of CS-induced inflammation and emphysema.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 These studies were funded by National Institutes of Health Grants HL-56389, HL-064242, and HL-078744 (to J.A.E.).
2 Address correspondence and reprint requests to Dr. Jack A. Elias, Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, P.O. Box 208057, 300 Cedar Street (S441 TAC), New Haven, CT 06520-8040. E-mail address: jack.elias{at}yale.edu
3 Abbreviations used in this paper: COPD, chronic obstructive pulmonary disease; BAL, bronchoalveolar lavage fluid; CS, cigarette smoke; GOLD, Global Initiative for Chronic Obstructive Lung Disease; IHC, immunohistochemistry; MMP, matrix metalloproteinase; RA, room air; WT, wild type.
This article has been cited by other articles:
|
|
 |
|
  M. T. Borchers, S. C. Wesselkamper, B. L. Eppert, G. T. Motz, M. A. Sartor, C. R. Tomlinson, M. Medvedovic, and J. W. Tichelaar Nonredundant Functions of {alpha}{beta} and {gamma}{delta} T Cells in Acrolein-Induced Pulmonary Pathology Toxicol. Sci., September 1, 2008; 105(1): 188 - 199. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. F. Chung and I. M. Adcock Multifaceted mechanisms in COPD: inflammation, immunity, and tissue repair and destruction Eur. Respir. J., June 1, 2008; 31(6): 1334 - 1356. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Churg, M. Cosio, and J. L. Wright Mechanisms of cigarette smoke-induced COPD: insights from animal models Am J Physiol Lung Cell Mol Physiol, April 1, 2008; 294(4): L612 - L631. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Imaoka, T. Hoshino, S. Takei, T. Kinoshita, M. Okamoto, T. Kawayama, S. Kato, H. Iwasaki, K. Watanabe, and H. Aizawa Interleukin-18 production and pulmonary function in COPD Eur. Respir. J., February 1, 2008; 31(2): 287 - 297. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Hoshino, H. A. Young, and H. Aizawa Cytokines in Pulmonary Emphysema: Can Results in Mice Be Translated to Humans? Am. J. Respir. Crit. Care Med., January 15, 2008; 177(2): 238 - 239. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
