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 alpha1antitrypsin (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)-beta1 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 < or = 0.01), particularly if only lungs with AAT-deficiency emphysema were considered (p < or = 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 < or = 0.05). TGF-beta1 expression in the alveolar wall was higher in patients with smoking-associated emphysema than in cases with AAT-deficiency emphysema (p < or = 0.05). A positive correlation between TGF-betaRII and AI was observed only in the control group (p < or = 0.005, r2 = 0.8). A negative correlation was found between the TGF-beta pathway (particularly TGF-betaRII) and T lymphocytes infiltrate in smoking-related cases (p < or = 0.05, r2 = 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 TGFbeta-1 pathway does not seem to directly influence epithelial turnover in end-stage disease. Inflammatory cytokine different from TGF-beta1 may differently orchestrate cell fate in AAT and smoking-related emphysema types

Expression of the Atypical Chemokine Receptor D6 in Human Alveolar Macrophages in COPD

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Dual polarization of human alveolar macrophages progressively increases with smoking and COPD severity

BACKGROUND: It is known that tissue macrophages derive not only from blood monocytes but also from yolk sac or fetal liver, and the tissue of residence guides their function. When isolated, they lose tissue specific signatures, hence studies of human macrophages should be ideally done directly in the tissue. The aim of this study was to investigate directly in human lung tissue the polarization of alveolar macrophage (AM), classic (M1) or alternative (M2), in health and disease, using COPD as a model. METHODS: Surgical lungs from 53 subjects were studied: 36 smokers whose FEV(1) varied from normal to severe COPD, 11 non-smokers and 6 normal donors. iNOS and CD206 immunohistochemistry was used to quantify the percentage of AM polarized as M1 or M2 in lung sections. RESULTS AND DISCUSSION: The percentage of M1 and M2 increased progressively with smoking and COPD severity, from 26% to 84% for M1 and from 7% to 78% for M2. In donors 74% of AM were negative for M1 and 93% for M2. Confocal microscopy showed co-localization of M1 and M2 in the same AM in severe COPD. CONCLUSION: In normal lungs alveolar macrophages were mostly non-polarized. With smoking and COPD severity, M1 and M2 polarization increased significantly and so did the co-expression of M1 and M2 in the same alveolar macrophage. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12931-017-0522-0) contains supplementary material, which is available to authorized users

Immune inflammation and disease progression in idiopathic pulmonary fibrosis

The clinical course in idiopathic pulmonary fibrosis (IPF) is highly heterogeneous, with some patients having a slow progression and others an accelerated clinical and functional decline. This study aims to clinically characterize the type of progression in IPF and to investigate the pathological basis that might account for the observed differences in disease behavior. Clinical and functional data were analyzed in 73 IPF patients, followed long-time as candidates for lung transplantation. The forced vital capacity (FVC) change/year (< or 6510% predicted) was used to define "slow" or "rapid" disease progression. Pathological abnormalities were quantified in the explanted lung of 41 out of 73 patients undergoing lung transplantation. At diagnosis, slow progressors (n = 48) showed longer duration of symptoms and lower FVC than rapid progressors (n = 25). Eleven slow and 3 rapid progressors developed an acute exacerbation (AE) during follow-up. Quantitative lung pathology showed a severe innate and adaptive inflammatory infiltrate in rapid progressors, markedly increased compared to slow progressors and similar to that observed in patients experiencing AE. The extent of inflammation was correlated with the yearly FVC decline (r = 0.52, p = 0.005). In conclusion an innate and adaptive inflammation appears to be a prominent feature in the lung of patients with IPF and could contribute to determining of the rate of disease progression

To reg or not to reg: that is the question in COPD

Editoriale, no abstrac

Pathophysiology of the small airways

Abstract This review describes, in some detail, the normal structure of the small airways, how this structure is achieved during the development of the bronchial tree from embryogenesis to adulthood, and how the structure determines the function of the airways at different ages and in disease. We then describe the structural abnormalities in small airways in chronic obstructive pulmonary disease (COPD) and their relationship with the disordered pulmonary function found in this disease, as an example of the mechanisms leading to airflow limitation in diseased airways. We address the pathology of small airways in different stages of COPD, summarizing the structural abnormalities associated with the progressive deterioration of pulmonary function from smokers with normal lung function to smokers with severe COPD. The importance of the elastic recoil in the normal and abnormal function of the airways is also highlighted

Severe asthma: inflammation

Severe asthma is a heterogeneous disease. Identification of specific sub-phenotypes of asthma may further improve our understanding of its pathophysiology. The genetic and environmental elements that may be important in the development of the disease are poorly understood, but it appears that the pathophysiological background of severe asthma includes both allergic and non-allergic elements. Inflammatory cells are usually present and activated in the airways of patients with severe asthma, and persist despite treatment, but their relevance to lack of asthma control and disease severity is largely unknown. Histopathological studies of severe asthma suggest that 1/2 to 2/3 of patients with severe asthma have persistent large airway tissue eosinophils, despite continued administration of high-dose systemic and inhaled steroids. Severe asthma has also been associated with neutrophilic inflammation, but the precise role of neutrophils is not yet clear. Up to 50% of patients with severe asthma, however, show no evidence of increased airway inflammation. "Steroid resistance" may occur at several levels, not all of which are related to lack of effect of steroids on inflammation. It appears that the factors leading to the development of severe asthma are complex and the disease is probably a mixture of various syndromes that have different elements, but also share similarities at the pathophysiological level. A better understanding of the immunological and histopathological phenotypes of severe asthma should enhance our ability both to understand the pathogenesis of these syndromes and to improve our therapeutic approach, leading to better targeting of both current and novel forms of treatment