A single intratracheal dose of porcine pancreatic elastase, which is cleared from the lung by 24 hours, was administered to wild-type, IL-1β type 1 receptor-deficient, double TNF-α (type 1 and type 2) receptor-deficient, and combined TNF-α (type 1 receptor) plus IL-1β receptor-deficient mice. The mean linear intercept (Lm) of saline-treated mice was 32(3) μm [mean(SE)]. For wild-type elastase-treated mice, Lm was 81(6) μm at 21 days versus 52(5) μm at 5 days after treatment, indicating that alveolar wall remodeling occurs long after the elastase injury. At 21 days, Lm values were 67(10), 62(3), and 39(5) μm in elastase-treated mice deficient in the IL-1β receptor, double TNF-α receptors, and combined receptors, respectively. The level of apoptosis assessed by a terminal deoxynucleotidyl transferase-catalyzed in situ nick end-labeling assay was increased at 5 days after elastase treatment and was markedly and similarly attenuated in the IL-1β, the double TNF-α, and the combined receptor-deficient mice. Our results indicate that inflammatory mediators exacerbate elastase-induced emphysema. We estimate that in the combined TNF-α + IL-1β receptor-deficient mice, inflammation accounts for about 80% of the emphysema that develops after elastase treatment; decreased apoptosis of lung cells likely contributes to decreased severity of emphysema.
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Portions of this work were presented at the annual meeting of the American Lung Association/American Thoracic Society, May 2001, San Francisco, California.
