Looking at the acinus with function tests: can you believe it?
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Humans↗
Biomedical subjects
Manuel G Cosio
Publications and source records attributed to Manuel G Cosio.
Cigarette smoke-induced Egr-1 upregulates proinflammatory cytokines in pulmonary epithelial cells.
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide and is a progressive and irreversible disorder. Cigarette smoking is associated with 80-90% of COPD cases; however, the genes involved in COPD-associated emphysema and chronic inflammation are poorly understood. It was recently demonstrated that early growth response gene 1 (Egr-1) is significantly upregulated in the lungs of smokers with COPD (Ning W and coworkers, Proc Natl Acad Sci 2004;101:14895-14900). We hypothesized that Egr-1 is activated in pulmonary epithelial cells during exposure to cigarette smoke extract (CSE). Using immunohistochemistry, we demonstrated that pulmonary adenocarcinoma cells (A-549) and primary epithelial cells lacking basal Egr-1 markedly induce Egr-1 expression after CSE exposure. To evaluate Egr-1-specific effects, we used antisense (alphaS) oligodeoxynucleotides (ODN) to knock down Egr-1 expression. Incorporation of Egr-1 alphaS ODN significantly decreased CSE-induced Egr-1 mRNA and protein, while sense ODN had no effect. Via Egr-1-mediated mechanisms, IL-1beta and TNF-alpha were significantly upregulated in pulmonary epithelial cells exposed to CSE or transfected with Egr-1. To investigate the relationship between Egr-1 induction by smoking and susceptibility to emphysema, we determined Egr-1 expression in strains of mice with different susceptibilities for the development of smoking-induced emphysema. Egr-1 was markedly increased in the lungs of emphysema-susceptible AKR/J mice chronically exposed to cigarette smoke, but only minimally increased in resistant NZWLac/J mice. In conclusion, Egr-1 is induced by cigarette smoke and functions in proinflammatory mechanisms that likely contribute to the development of COPD in the lungs of smokers.
Animals↗
Characterization of T lymphocytes in chronic obstructive pulmonary disease.
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Humans↗
The development of emphysema in cigarette smoke-exposed mice is strain dependent.
Only 20% of smokers develop chronic obstructive pulmonary disease. An important determinant of susceptibility is genomic variation. We undertook this study to define strains of mice with different susceptibilities for the development of smoking-induced emphysema because they could help identify genetic factors of susceptibility. NZWLac/J, C57BL6/J, A/J, SJ/L, and AKR/J strains were exposed to cigarette smoke for 6 months. Elastance (Htis), the extent of emphysema (mean linear intercept [Lm]), and the inflammatory cell and cytokine response were measured. NZWLac/J had no change in Lm or Htis (resistant). C57BL6/J, A/J, and SJ/L increased Lm, but not Htis (mildly susceptible). AKR/J increased Lm and Htis (super-susceptible). Only AKR/J had significant inflammation comprising macrophages, neutrophils, and T cells. The AKR/J showed an upregulation of Th1 cytokines whereas in the C57BL/6/J and NZWlac/J, cytokines did not change or were downregulated. We conclude that Lm, elastance, and inflammation are features that are needed to phenotype emphysema in mice. The inflammatory cell and cytokine profile may be an important determinant of the phenotype in response to cigarette smoke exposure. The identification of resistant and susceptible strains for the development of emphysema could be useful for genomic studies of emphysema susceptibility in mice and eventually in humans.
Animals↗
Reference values of pulmonary function tests for Canadian Caucasians.
A multicentre, cross-sectional study was carried out in six centres across Canada to establish a national standard for pulmonary function tests using healthy, lifetime nonsmokers, with each centre aiming to test 10 men and 10 women from each decade from 20 to 80 years of age. Data from each centre were used to derive prediction equations for each centre, and pooled data from all centres (total: 327 women and 300 men) were used to derive Canadian predicted equations. The predictive models were compared with three widely used published models for selected tests. It was found that, in general, the equations modelled for each centre could be replaced by the models obtained when pooling all data (Canadian model). Comparisons with the published references showed good agreement and similar slopes for most tests. The results suggest that pulmonary function test results obtained from different centres in Canada were comparable and that standards currently used remain valid for Canadian Caucasians.
Adult↗
Pathophysiology of the small airways.
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.
Journal Article↗
Alpha1-antitrypsin determines the pattern of emphysema and function in tobacco smoke-exposed mice: parallels with human disease.
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.
Animals↗
Inflammation of the airways and lung parenchyma in COPD: role of T cells.
A smoking-induced inflammatory reaction in the airways and lung parenchyma, comprised mainly of neutrophils and alveolar macrophages, has long been accepted to be the major cause of COPD in smokers. Recent reports have underlined the role of the T lymphocyte as a potentially important factor in the inflammatory process leading to COPD. It has been found that, in the airways and the lung parenchyma, the presence of T cells, predominantly CD8+ T cells, can distinguish between smokers with and without COPD. In addition to T cells, other inflammatory cell types such as neutrophils and macrophages are probably essential in the initial inflammatory process leading to the breakdown of lung tissue, perhaps producing peptides eventually recognized by T cells as antigenic. This would provide an explanation for the T-cell inflammation. Once activated, T cells are present in the lung, and their effector functions would include the attraction and enhancement of the inflammatory function in other inflammatory cells like neutrophils and macrophages. It seems likely that, only when all inflammatory cell types (ie, CD4+, CD8+, neutrophils, and macrophages) are present in the lung, the airways remodeling and parenchymal destruction characteristic of COPD will ensue. If T cells are responsible for the lung injury and progression of COPD, it would resemble a response to an antigenic stimulus originating in the lung. If that were the case, COPD could be considered to be an autoimmune disease triggered by smoking.
Animals↗