α₁-Antitrypsin Determines the Pattern of Emphysema and Function in Tobacco Smoke–exposed Mice

Abstract

Cigarette smoking in humans is associated with various patterns of emphysema and functional consequences. We tested the hypothesis that variations in alpha1-antitrypsin expression modulate the pattern of emphysema and functional consequences in cigarette smoke-exposed mice. We compared the effects of up to 6 months of cigarette smoke exposure in C57BL/6J (C57) mice and in low-alpha1-antitrypsin, C57BL/6J pa+/pa+ (pallid) mice. At the end of the experiment, we determined lung mechanical properties, the extent (mean linear intercept) and type of emphysema, and the cellular inflammatory response. After 4 months of cigarette smoking, pallid smoking mice, but not C57 smoking mice, had a significant increase in mean linear intercept. After 6 months of smoke exposure, C57 smoking mice and pallid smoking mice had similar degrees of emphysema. The pattern of emphysema in pallid smoking mice was more diffuse than in C57 smoking mice, affecting all airspaces. Pallid mice, but not C57 mice, developed a T cell inflammation in the alveolar wall after 6 months of smoking (p < 0.01). Although lung compliance was not changed in C57 smoking mice after smoke exposure, it increased significantly in pallid smoking mice over the 6 months of exposure (p < 0.0082). In summary, cigarette smoking induces emphysema in C57 and pallid mice, but the emphysema, inflammatory infiltrate, and resulting physiologic abnormalities were substantially different in the two strains, with the C57 and pallid mice exhibiting features similar to centrilobular and panlobular emphysema, respectively.

Functional evaluation of pallid mice with genetic emphysema

“…In addition to the knowledge regarding the biochemical, morphological, and functional aspects of pallid mice as an emphysema model, which have been previously reported, [10][11][12][13][14] new findings were revealed in this functional study on mice. Therefore, this model for the evaluation of The pallid mice at 12 months of age showed a significantly higher Lm than the age-matched C57BL/6J mice.…”

“…Lm has been used as an index to indicate expanding alveolar spaces, and it is often used in studies that use pallid mice as an emphysema model. [10][11][12][13][14] It is Age, months (10) (11) (12) (10) (9) (11) (9) (11) In the pallid mice, the FEV 20 ms /VC at 3 months of age was significantly higher than those at 12 months (Po0.01) and 15 months (Po0.01) of age. One-way analysis of variance did not reveal any statistically significant differences in C57BL/6J mice.…”

“…Morphological, biochemical, and genetic analyses have been performed on these mice. [10][11][12][13][14] Morphological evaluations such as mean linear (Lm) intercept determinations are insufficient, and a functional evaluation is required. However, few studies have addressed the pulmonary function and exercise capacity in pallid mice.…”

Avaliação quantitativa das fibras elásticas na doença pulmonar obstrutiva crônica

“…Under normal conditions, the proteolytic enzyme activity is prevented and restored by the antiproteolytic enzymes. (7)(8)(9) This fact has stimulated some researchers to produce emphysema models involving high concentrations of elastase or alpha-1 antitrypsin deficiency. (9)(10)(11) However, the correlation between these inflammatory models and the structural alterations produced by them is not simple or direct.…”

Células inflamatórias e seus mediadores na patogênese da DPOC

“…Em modelo animal de enfisema induzido pela exposição à fumaça de cigarro foi observado que, além do número de linfócitos T estarem aumentado, havia correlação direta entre esse número e a gravidade da doença pulmonar 25 .…”