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Tobacco, Inflammation, and Respiratory Tract Cancer.

Cigarette smoking is the most recognized risk factor for many inflammatory diseases such as cardiovascular diseases, chronic obstructive pulmonary disease and for a number of malignances such as lung cancer. Lung cancer is currently considered the leading cause of cancer-related deaths because its aggressive nature and the lack of effective therapeutic options.

Recent advances in molecular biology and immunology have improved the knowledge on different mechanisms implicated in lung cell malignant transformation, progression and metastasis, thus presenting an exciting new era for lung anticancer therapies. The way by which cigarette smoke may induce lung malignancy includes a large number of different mechanisms and substances, most of them currently unknown. Thus, identified carcinogenic compounds of cigarette smoke may induce themselves a direct cytotoxicity and mutagenic action on lung epithelial cells by means of generation of somatic mutations, epigenetic events, epithelial cell to mesenchymal cell transformations, as well as by chronic cell damage. However, the fact that there is a relative high prevalence of ex-smoker who may develop lung cancer after years of smoking cessation suggest that other causes are also implicated. Thus cigarette smoke-induced chronic lung inflammatory microenvironment, oxidative stress and cell structural alterations such as the increase of cell proliferation, angiogenesis and apoptosis arrest are irreversible processes that have a high influence in lung tumor growth.

In this review we focused in current knowledge on the mechanisms implicated in cigarette smoke-induced lung chronic inflammatory processes leading to lung carcinogenesis, as well as in current therapies based on novel molecular advances.

Reactive Oxygen Species, Inflammation, and Lung Diseases.

Reactive oxygen species (ROS) are well recognized for playing a dual role as both deleterious and beneficial species. ROS are products of normal cellular metabolism and under physiological conditions, participate in maintenance of cellular redox homeostasis. Overproduction of ROS, results in oxidative stress. Oxidative stress is a deleterious process that leads to lung damage and consequently to various disease states.

The lung is a highly specialized organ that facilitates uptake of oxygen and release of carbon dioxide. Persistent inhalation of the invading pathogens or toxic agents may result in overwhelming production of ROS. Oxidants initiate a number of pathologic processes, including inflammation of the airways, which may contribute to the pathogenesis and/or exacerbation of airways disease. During inflammation, enhanced ROS production may induce recurring DNA damage, inhibition of apoptosis, and activation of proto-oncogenes by initiating signal transduction pathways. Therefore, it is conceivable that chronic inflammation-induced production of ROS in the lung may predispose individuals to lung diseases.

In this review, we discuss mechanisms of oxidant stress in the lung, the role of oxidants in lung disease pathogenesis and exacerbation.

Pro-inflammatory and immunomodulatory functions of the airway smooth muscle: Emerging concepts.

Airway smooth muscle (ASM) is the main regulator of bronchomotor tone. Extensive studies show that in addition to their physical property, human airway smooth muscle (ASM) cells can participate in inflammatory processes modulating the initiation, perpetuation, amplification, and perhaps resolution of airway inflammation. Upon stimulation or interaction with immune cells, ASM cells produce and secrete a variety of inflammatory cytokines and chemokines, cell adhesion molecules, and extracellular matrix (ECM) proteins.

These released mediators can, in turn, contribute to the inflammatory state, airway hyperresponsiveness, and airway remodeling present in asthma. As our knowledge of ASM myocyte biology improves, novel bioactive factors are emerging as potentially important regulators of inflammation.

This review provides an overview of our understanding of some of these molecules, identifies rising questions, and proposes future studies to better define their role in ASM cell modulation of inflammation and immunity in the lung and respiratory diseases.

Expanding the Clinical Indications for Alpha-1-Antitrypsin Therapy.

Alpha-1-antitrypsin (AAT) is a 52-kDa circulating serine protease inhibitor. Production of AAT by the liver maintains 0.9-1.75 mg/ml circulating levels. During acute phase responses, circulating AAT levels incraese >4-fold. In individuals with one of several inherited mutations in AAT, low circulating levels increase the risk for lung, liver and pancreatic destructive diseases, particularly emphysema.

These individuals are treated with life-long weekly infusions of human plasma-derived AAT. An increasing amount of evidence appears to suggest that AAT possesses not only the ability to inhibit serine proteases, such as elastase and proteinase-3, but also to exert anti-inflammatory and tissue protective effects independent of protease inhibition. AAT modifies dendritic cell maturation and promotes T regulatory cell differentiation, induces interleukin-1 receptor antagonist and interleukin-10 release, protects various cell types from cell death, inhibits caspases-1 and -3 activity and inhibits interleukin-1 production and activity. Importantly, unlike classic immunosuppressants, AAT allows undetered isolated T-lymphocyte responses.

Based on preclinical and clinical studies, AAT therapy for non-deficient individuals may interfere with disease progression in Type-1 and Type-2 diabetes, acute myocardial infarction, rheumatoid arthritis, inflammatory bowel disease, cystic fibrosis, transplant rejection, graft-versus-host-disease and multiple sclerosis. AAT also appears to be antibacterial and an inhibitor of viral infections, such as influenza and HIV, and is currently evaluated in clinical trials for Type-1 diabetes, cystic fibrosis and graft-versus-host-disease.

Thus, AAT therapy appears to have advanced from replacement therapy, to a safe and potential treatment for a broad spectrum of inflammatory and immune-mediated diseases.

Diagnostic accuracy of clinical symptoms in obstructive airway diseases varied within different health care sectors.

To determine the diagnostic accuracy and diagnostic patterns of clinical symptoms in patients suspected to suffer from obstructive airway diseases (OADs) within different health care sectors.

STUDY DESIGN AND SETTING: Ten general practices (219 patients), one practice of pneumologists (259 patients) and one specialist hospital (300 patients). Sensitivities, specificities, positive (LR+), and negative (LR-) likelihood ratios of clinical symptoms were compared with lung function testing.

RESULTS: Thirty-one percent had chronic obstructive pulmonary disease (COPD), 21% had asthma. Sensitivities increased and specificities decreased from outpatient to hospital setting. The multivariate model of adjusted likelihood ratios for COPD showed LR+=4.86 (95% confidence interval [CI]=2.09-11.29) and LR-=0.07 (95% CI=0.01-0.43) of the combination "wheezing," "dyspnea when going upstairs," "smoking" in general practice. In hospital, the combination "dyspnea when going upstairs," "dyspnea during minimal exercise," and "smoking" showed LR+=3.34 (95% CI=2.08-5.31) and LR-=0.02 (95% CI=0.01-0.12). The combination "no coughing," "dyspnea attacks," and "no smoking" showed LR+=4.08 (95% CI=1.67-10.4) and LR-=0.24 (95% CI=0.12-0.58) for asthma in general practice. The combination "dyspnea attacks" and "no dyspnea when walking" showed LR+=6.48 (95% CI=1.01-40.94) and LR-=0.28 (95% CI=0.11-0.75) for asthma in hospital.

CONCLUSION: Clinical decision rules for OAD need to be derived from original studies in their respective settings or assessed on their transferability to other settings.

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