Abstract
BackgroundApoptosis has recently been proposed to contribute to the pathogenesis of emphysema.MethodsIn order to establish if cell fate plays a role even in end-stage disease we studied 16 lungs (9 smoking-associated and 7 α1antitrypsin (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)-β1 pathway was also investigated and correlated with epithelial cell turnover and with the severity of inflammatory cell infiltrate.ResultsThe 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-β1 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-βRII and AI was observed only in the control group (p ≤ 0.005, r2 = 0.8). A negative correlation was found between the TGF-β pathway (particularly TGF-βRII) and T lymphocytes infiltrate in smoking-related cases (p ≤ 0.05, r2 = 0.99)ConclusionOur findings suggest that apoptosis of alveolar epithelial cells plays an important role even in end-stage emphysema particularly in AAT-deficiency disease. The TGFβ-1 pathway does not seem to directly influence epithelial turnover in end-stage disease. Inflammatory cytokine different from TGF-β1 may differently orchestrate cell fate in AAT and smoking-related emphysema types.
Highlights
Apoptosis has recently been proposed to contribute to the pathogenesis of emphysema
An increased pro-apoptotic milieu of inflammatory related cytokines may contribute to the higher cell death rate detected in AATdeficiency emphysema
In our work a direct correlation between transforming growth factor (TGF)-βRII and apoptotic index (AI) was found in the control group showing that this cytokine could play a role in alveolar homeostasis in physiologic conditions
Summary
Apoptosis has recently been proposed to contribute to the pathogenesis of emphysema. The concept is that activated inflammatory cells release large quantities of elastases, overwhelming local antiprotease activity with consequent damage to the alveolar wall matrix [3]. The emphasis on alveolar matrix destruction by a combination of inflammation and excessive proteolysis has failed to fully explain the loss of lung tissue, when compared to alterations seen in other inflammatory lung diseases. The presence of apoptosis has recently been described in animal models of emphysema [4,5] and in a few studies of human disease [6,7,8,9]
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