Marked alveolar apoptosis/proliferation imbalance in end-stage emphysema

Background: Apoptosis has recently been proposed to contribute to the pathogenesis of emphysema. Methods: In order to establish if cell fate plays a role even in end-stage disease we studied 16 lungs ( 9 smoking-associated and 7 alpha 1 antitrypsin (AAT)-deficiency emphysema) from patients who had undergone lung transplantations. Six unused donor lungs served as controls. Apoptosis was evaluated by TUNEL analysis, single-stranded DNA laddering, electron microscopy and cell proliferation by an immunohistochemical method (MIB1). The role of the transforming growth factor (TGF)-beta 1 pathway was also investigated and correlated with epithelial cell turnover and with the severity of inflammatory cell infiltrate. Results: The apoptotic index ( AI) was significantly higher in emphysematous lungs compared to the control group ( p <= 0.01), particularly if only lungs with AAT-deficiency emphysema were considered ( p <= 0.01 vs p = 0.09). The proliferation index was similar in patients and controls (1.9 +/- 2.2 vs 1.7 +/- 1.1). An increased number of T lymphocytes was observed in AAT-deficiency lungs than smoking-related cases ( p <= 0.05). TGF-beta 1 expression in the alveolar wall was higher in patients with smoking-associated emphysema than in cases with AAT-deficiency emphysema ( p <= 0.05). A positive correlation between TGF-beta RII and AI was observed only in the control group ( p <= 0.005, r(2) = 0.8). A negative correlation was found between the TGF-beta pathway ( particularly TGF-beta RII) and T lymphocytes infiltrate in smoking- related cases ( p <= 0.05, r(2) = 0.99) Conclusion: Our findings suggest that apoptosis of alveolar epithelial cells plays an important role even in end-stage emphysema particularly in AAT-deficiency disease. The TGF-beta 1 pathway does not seem to directly influence epithelial turnover in end-stage disease. Inflammatory cytokine different from TGF-beta 1 may differently orchestrate cell fate in AAT and smoking- related emphysema types.