Emphysema genetics

J. Bignon and G. L. Scarpa (Eds.), Biochemistry, Pathology and Genetics of Pulmonary Emphysema Proceedings of a Meeting held at Porto Conte, Sassari, April 27-30, 1981, Pergamon, New York, 1981. 

Correct answer = B. o1-Antitrypsin deficiency is a genetic disorder that can cause pulmonary emphysema even in the absence of cigarette use. An deficiency of a1-antitrypsin permits increased elastase activity to destroy elastin in the alveolar walls, even in nonsmokers. a1-antitrypsin deficiency should be suspected when chronic obstructive pulmonary disease develops in a patient younger than 45 years who does not have a history of chronic bronchitis or tobacco use, or when multiple family members develop obstructive lung disease at an early age. 

Crystal, R. G. (1990). Alpha 1 -antitrypsin deficiency, emphysema, and liver disease Genetic basis and strategies for therapy. J. Clin. Invest. 85, 1343-1352. 

In particular, excessive proteolysis of elastin by HLE has been implicated in pulmonary emphysema [19]. In this case, the imbalance appears to result from reduced levels of active extracellular alpha,-proteinase inhibitor (a,-PI), the primary plasma inhibitor of HLE. This decrease is caused either by a genetic disorder (PiZZ phenotype individuals) or by reduction in the elastase inhibitory capacity (EIC) of ai-PI due to its oxidative inactivation by tobacco smoke [20]. The detailed evidence supporting the potential role of elastase in the development of emphysema has been extensively reviewed [21] and will not be repeated here. The fact that HLE is also a potent secretagogue [22] may play a role in several disease states, including cystic fibrosis [23], chronic bronchitis [24], and acute respiratory distress syndrome (ARDS) [25]. The mechanism of the secretagogue activity is not known, but, since the HLE-induced secretion can be blocked by specific HLE inhibitors, it appears to require catalytic activity by the enzyme [26]. 

Because of the advances in biotechnology that have resulted not only in new macromolecules but also in new devices to deliver them via the lungs, patients and physicians will soon be able to use this route to treat diseases such as diabetes, hepatitis, osteoporosis, multiple sclerosis, genetic emphysema, cystic fibrosis, and other pulmonary infections among others. 

Chronic obstructive pulmonary disease is a respiratory condition characterized by irreversible airway obstruction caused by chronic bronchitis or emphysema. The major symptoms of COPD include chronic cough, increased sputum production, and dyspnea. The vast majority of patients with COPD are those who are current or former heavy smokers. Other risk factors for the development of COPD include occupational exposure (dusts, chemicals) and rare genetic disorders (a -antitrypsin deficiency). The medical management of COPD includes pharmacotherapy (bronchodilators, corticosteroids, and antibiotics) in combination with interventions to reduce risk factors for disease progression (e.g., smoking cessation). Some patients require long-term administration of supplemental oxygen. 

A reduction of the proteinase inhibitory activity is due to oxidation of the reactive methionine residue of the active center by the cigarette smoke as well as by oxygen radicals produced by leukocytes and macrophages. Emphysema is a common disease, and its most common cause is cigarette smoking. Only 1-2% of cases are due to genetic deficiency of apAT. 

Some people have a genetic predisposition to emphysema. This is called familial emphysema. These individuals have been found to have a genetic defect in the gene that encodes the human plasma protein Uj-antitrypsin. As the name suggests, Ui-antitrypsin is an inhibitor of the proteolytic enzyme trypsin. But, as we have seen in this chapter, trypsin is just one member of a large family of proteolytic enzymes called the serine proteases. In the case of the oii-antitrypsin activity in the lung, it is the inhibition of the enzyme elastase that is the critical event. 

Elastase damages or destroys elastin, which in turn promotes the development of emphysema. People with normal levels of Ui-antitrypsin are protected from familial emphysema because their aj-antitrypsin inhibits elastase and, thus, protects the elastin. The result is healthy alveoli in the lungs. However, individuals with a genetic predisposition to emphysema have... 

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