ToxSci Advance Access originally published online on May 12, 2006
Toxicological Sciences 2006 92(2):545-559; doi:10.1093/toxsci/kfl016
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Modulators of Cigarette Smoke–Induced Pulmonary Emphysema in A/J Mice
Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108
Received March 15, 2006; accepted May 10, 2006
Mice develop pulmonary emphysema after chronic exposure to cigarette smoke (CS). In this study, the influence of gender, exposure duration, and concentration of CS on emphysema, pulmonary function, inflammation, markers of toxicity, and matrix metalloproteinase (MMP) activity was examined in A/J mice. Mice were exposed to CS at either 100 or 250 mg total particulate material/m3 (CS-100 or CS-250, respectively) for 10, 16, or 22 weeks. Evidence of emphysema was first seen in female mice after 10 weeks of exposure to CS-250, while male mice did not develop emphysema until 16 weeks. Female mice exposed to CS-100 did not have emphysema until 16 weeks, suggesting that disease development depends on the concentration and duration of exposure. Airflow obstruction and increased pulmonary compliance were observed in mice exposed to CS-250 for 22 weeks. Decreased elasticity was likely the major contributor to airflow obstruction because substantial remodeling of the conducting airways, beyond mild mucous cell hyperplasia, was lacking. Exposure to CS increased the number of macrophages, neutrophils, lymphocytes (B cells and activated CD4- and CD8-positive T cells), and activity of MMP-2 and -9 in the bronchoalveolar lavage fluid (BALF). Treatment with antioxidants N-acetylcysteine or epigallocatechin gallate (EGCG) did not decrease emphysema severity, but EGCG slightly decreased BALF inflammatory cell numbers and lactate dehydrogenase activity. Inflammation and emphysema persisted after a 17-week recovery period following exposure to CS-250 for 22 weeks. The similarities of this model to the human disease make it promising for studying disease pathogenesis and assessing new therapeutic interventions.
Key Words: A/J mice; animal models; cigarette smoke; pulmonary emphysema; morphometry; pulmonary function.
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