Alpha1-Antitrypsin Deficiency in COPD: Clinical Implications

, College of Physicians and Surgeons, Columbia University, NY

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In This Article

Pathophysiology of Airway Inflammation in Chronic Airway Disease

Chronic bronchitis, emphysema and asthma represent a spectrum of airway disease that share common inflammatory pathways and involve the participation of neutrophils.[13]

Asthma is a condition of extreme airways hyperreactivity and involves a number of cell types and pathways of cytokine release, as shown in Figure 3. Activation of these pathways induces the asthmatic state which involves smooth muscle contraction, vascular dilatation and mucosal edema. Asthma results from a prolonged inflammatory process affecting the airways and, as in other forms of COPD, a variety of mediator driven pathways are involved.

Cellular mechanisms of airway inflammation in asthma.

Theoretical basis for the modulation of neutrophil-induced inflammation by alpha1-ATD. Several lines of evidence indicate that optimal local concentrations of alpha1-AT in the lung inhibit some of the pro-inflammatory pathways that enhance recruitment and activation of neutrophils. Two examples of the mechanisms involved are shown in Figure 4. Alveolar macrophages from patients with alpha1-ATD are stimulated by unbound neutrophil elastase to release leukotriene B4, a powerful neutrophil attractant.[14] Under normal conditions neutrophil elastase is bound to alpha1-AT and is unable to effect this release. Furthermore, interleukin 1, tumor necrosis factor and neutrophil elastase induce the synthesis and release of platelet activating factor, a potent chemotactic agent for neutrophils, from a variety of cell types, including macrophages.[15] Platelet activating factor release is inhibited by unoxidized alpha1-AT (Fig. 4).

Neutrophil accumulation in alpha 1-ATD.

In a sheep model simulating asthma, airway hyperresponsiveness to Ascaris antigen was inhibited by pretreatment with alpha1-AT. This effect was associated with an inhibition of tissue kallikrein activity, a mediator of bronchoconstriction and airway hyperresponsiveness.[16] Alpha1-AT attenuates the release of cytokines during inflammation. In the absence of optimal anti-elastase activity, inflammation and airways hyperreactivity may develop, leading to increased degradation of lung tissue.

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