Anthony Tam

The airway epithelium: more than just a structural barrier.

The mammalian airway is lined by a variety of specialized epithelial cells that not only serve as a physical barrier but also respond to environment-induced damage through the release of biologically active factors and constant cellular renewal. The lung epithelium responds to environmental insults such as pathogens, cigarette smoke and pollution by secreting inflammatory mediators and antimicrobial peptides, and by recruiting immune cells to the site of infection or damage. When the epithelium is severely damaged, basal cells and Clara cells that have stem-cell-like properties are capable of self-renewal and proliferation in the affected area, to repair the damage. In order to effectively fight off infections, the epithelium requires the assistance of neutrophils recruited from the peripheral circulation through transendothelial followed by transepithelial migration events. Activated neutrophils migrate across the epithelium through a series of ligand–receptor interactions to the site of injury, where they secrete proteolytic enzymes and oxidative radicals for pathogen destruction. However, chronic activation and recruitment of neutrophils in airway diseases such as chronic obstructive pulmonary disease and asthma has been associated with tissue damage and disease severity. In this paper, we review the current understanding of the airway epithelial response to injury and its interaction with inflammatory cells, in particular the neutrophil.

The role of female hormones on lung function in chronic lung diseases

BackgroundThe prevalence, morbidity, and mortality of inflammatory lung diseases such as asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) are increasing in women. There is a dearth of data on the biological mechanisms to explain such observations. However, some large epidemiologic studies suggest that lung function fluctuates during the menstrual cycle in female patients with airways disease but not in women without disease, suggesting that circulating estradiol and progesterone may be involved in this process.DiscussionIn asthma, estradiol shuttles adaptive immunity towards the TH2 phenotype while in smokers estrogens may be involved in the generation of toxic intermediate metabolites in the airways of female smokers, which may be relevant in COPD pathogenesis. In CF, estradiol has been demonstrated to up-regulate MUC5B gene in human airway epithelial cells and inhibit chloride secretion in the airways. Progesterone may augment airway inflammation.SummaryTaken together, clinical and in-vivo data have demonstrated a sex-related difference in that females may be more susceptible to the pathogenesis of lung diseases. In this paper, we review the effect of female sex hormones in the context of these inflammatory airway diseases.

Sex Differences in Airway Remodeling in a Mouse Model of Chronic Obstructive Pulmonary Disease

RATIONALE After adjustment for the amount of smoking, women have a 50% increased risk of chronic obstructive pulmonary disease (COPD) compared with men. The anatomic basis and/or mechanism(s) of these sex-related differences in COPD are unknown. OBJECTIVES To characterize the impact of female sex hormones on chronic cigarette smoke-induced airway remodeling and emphysema in a mouse model of COPD. METHODS Airway remodeling and emphysema were determined morphometrically in male, female, and ovariectomized mice exposed to 6 months of cigarette smoke. Antioxidant- and transforming growth factor (TGF)-β-related genes were profiled in airway tissues. The selective estrogen receptor modulator tamoxifen was also administered during smoke exposure in a short-term model. Airway wall thickness of male and female human smokers at risk of or with mild COPD was measured using optical coherence tomography. MEASUREMENTS AND MAIN RESULTS Small airway wall remodeling was increased in female but not male or ovariectomized mice and was associated with increased distal airway resistance, down-regulation of antioxidant genes, increased oxidative stress, and activation of TGF-β1. These effects were prevented by ovariectomy. Use of tamoxifen as a therapeutic intervention mitigated smoke-induced increase in oxidative stress in female mice. Compared with male human smokers, female human smokers had significantly thicker airway walls. CONCLUSIONS The excess risk of small airway disease in female mice after chronic smoke exposure was associated with increased oxidative stress and TGF-β1 signaling and also was related to the effects of female sex hormones. Estrogen receptor antagonism might be of value in reducing oxidative stress in female smokers.

Pro–Surfactant Protein B As a Biomarker for Lung Cancer Prediction

PURPOSE Preliminary studies have identified pro-surfactant protein B (pro-SFTPB) to be a promising blood biomarker for non-small-cell lung cancer. We conducted a study to determine the independent predictive potential of pro-SFTPB in identifying individuals who are subsequently diagnosed with lung cancer. PATIENTS AND METHODS Pro-SFTPB levels were measured in 2,485 individuals, who enrolled onto the Pan-Canadian Early Detection of Lung Cancer Study by using plasma sample collected at the baseline visit. Multivariable logistic regression models were used to evaluate the predictive ability of pro-SFTPB in addition to known lung cancer risk factors. Calibration and discrimination were evaluated, the latter by an area under the receiver operating characteristic curve (AUC). External validation was performed with samples collected in the Carotene and Retinol Efficacy Trial (CARET) participants using a case-control study design. RESULTS Adjusted for age, sex, body mass index, personal history of cancer, family history of lung cancer, forced expiratory volume in one second percent predicted, average number of cigarettes smoked per day, and smoking duration, pro-SFTPB (log transformed) had an odds ratio of 2.220 (95% CI, 1.727 to 2.853; P < .001). The AUCs of the full model with and without pro-SFTPB were 0.741 (95% CI, 0.696 to 0.783) and 0.669 (95% CI, 0.620 to 0.717; difference in AUC P < .001). In the CARET Study, the use of pro-SFPTB yielded an AUC of 0.683 (95% CI, 0.604 to 0.761). CONCLUSION Pro-SFTPB in plasma is an independent predictor of lung cancer and may be a valuable addition to existing lung cancer risk prediction models.

Pathobiologic Mechanisms of Chronic Obstructive Pulmonary Disease

COPD is a worldwide public health problem that reduces the quality of life. The exact pathways by which CS and other environmental toxins produce COPD are not known. Currently, the leading candidates are (1) the protease-antiprotease hypothesis, (2) the Dutch hypothesis, (3) the British hypothesis, and the (4) autoimmunity hypothesis. Given the heterogeneity of the disease (and phenotypes), it is probably unrealistic that one pathway will fully explain COPD pathophysiology.

Estradiol Increases Mucus Synthesis in Bronchial Epithelial Cells

Airway epithelial mucus hypersecretion and mucus plugging are prominent pathologic features of chronic inflammatory conditions of the airway (e.g. asthma and cystic fibrosis) and in most of these conditions, women have worse prognosis compared with male patients. We thus investigated the effects of estradiol on mucus expression in primary normal human bronchial epithelial cells from female donors grown at an air liquid interface (ALI). Treatment with estradiol in physiological ranges for 2 weeks caused a concentration-dependent increase in the number of PAS-positive cells (confirmed to be goblet cells by MUC5AC immunostaining) in ALI cultures, and this action was attenuated by estrogen receptor beta (ER-β) antagonist. Protein microarray data showed that nuclear factor of activated T-cell (NFAT) in the nuclear fraction of NHBE cells was increased with estradiol treatment. Estradiol increased NFATc1 mRNA and protein in ALI cultures. In a human airway epithelial (1HAE0) cell line, NFATc1 was required for the regulation of MUC5AC mRNA and protein. Estradiol also induced post-translational modification of mucins by increasing total fucose residues and fucosyltransferase (FUT-4, -5, -6) mRNA expression. Together, these data indicate a novel mechanism by which estradiol increases mucus synthesis in the human bronchial epithelium.

Sex-Related Differences in Pulmonary Function following 6 Months of Cigarette Exposure: Implications for Sexual Dimorphism in Mild COPD.

Female smokers have increased risk of chronic obstructive pulmonary disease (COPD) compared with male smokers who have a similar history of cigarette smoke exposure. We have shown previously that chronic smoke exposure for 6 months leads to increased airway wall remodeling in female C57BL/6 mice compared with male C57BL/6 mice. These differences, however, were not evident in female ovariectomized mice exposed to cigarette smoke. Herein, we report on the pulmonary function test results from the flexiVent system, which was used to determine the potential functional consequences of the histologic changes observed in these mice. We found that tissue damping (G) was increased in female compared to male or ovariectomized female mice after smoke exposure. At low oscillating frequencies, complex input resistance (Zrs) and impedance (Xrs) of the respiratory system was increased and decreased, respectively, in female but not in male or ovariectomized female mice after smoke exposure. Quasistatic pressure-volume curves revealed a reduction in inspiratory capacity in female mice but not in male or ovariectomized female mice after smoke exposure. The remaining lung function measurements including quasistatic compliance were similar amongst all groups. This is the first study characterizing a sexual dimorphism in respiratory functional properties in a mouse model of COPD. These findings demonstrate that increased airway remodeling in female mice following chronic smoke exposure is associated with increased tissue resistance in the peripheral airways. These data may explain the importance of female sex hormones and the increased risk of airway disease in female smokers.

Why are women more vulnerable to chronic obstructive pulmonary disease

Expert Rev. Respir. Med. 7(3), 197–199 (2013) “…female smokers demonstrated faster decline in lung function and a higher risk of hospitalization for chronic obstructive pulmonary disease compared with male smokers after controlling for pack years of smoking.”

Current methods to diagnose small airway disease in patients with COPD

ABSTRACT The small airways are characterized by an internal diameter < 2 mm and absence of cartilage. Approximately 10–25% of total airway resistance in healthy lungs is due to the small airways, with their contribution to total airway resistance increasing substantially in chronic obstructive pulmonary disease (COPD). As the small airways are located in the lung periphery, they are not easily evaluable, which can potentially interfere with the diagnosis (especially at early stages), monitoring, detection of responses to clinical interventions, and prognostic evaluation in COPD. Here, we will discuss the currently available methods in clinical practice to evaluate small airway disease in COPD, focusing on the concept, advantages, and disadvantages of each method.