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The role of alpha-1-antitrypsin in the development of pulmonary emphysema Dhami, Rajwinder Kaur

Abstract

BACKGROUND: Cigarette smoke is the most important etiologic agent in the development of emphysema (defined as airspace enlargement in the lungs) which accounts for a growing number of deaths annually worldwide. The protease-antiprotease hypothesis has been proposed to explain the pathogenesis of emphysema and states that an excessive proteolytic burden in the lung causes breakdown of connective tissue, leading to emphysema, although the specific proteases and antiproteases are not known. METHODS: Transgenic mice expressing the human alpha-1-antitrypsin (α1AT) gene were created and characterized. Markers of connective tissue breakdown, inflammatory cell numbers and elastase activities in the bronchoalveolar lavage after cigarette smoke or bacterial lipopolysaccharide (LPS) exposure were measured. Mice were given weekly intratracheal LPS and lung morphology was assessed. RESULTS: Four transgenic lines expressed human a α1AT in either type II alveolar cells or type II alveolar and airway epithelial cells. Levels of human α1AT protein in the lung were low but protein was present in the pulmonary interstitium. The transgenic mice were immunologically tolerant to human α1AT . Acute cigarette smoke exposure resulted in increased elastin and collagen breakdown products in the lavage which correlated with increases in lavage PMNs. LPS instillation resulted in elastin breakdown associated with increased lavage PMN numbers, and collagen breakdown associated with an increase in macrophage numbers. Administration of A A T prevented the connective tissue breakdown in the smoke-exposed mice and prevented elastin breakdown, but not collagen breakdown in the LPS treated mice. Mice receiving weekly intratracheal instillations of LPS developed emphysema. CONCLUSIONS: α1AT expression in pulmonary cells results in delivery of the protein to the pulmonary interstitium where connective tissue components are vulnerable to proteolytic attack. These mice, because of their tolerance to human α1AT, are useful for long-term studies on the efficacy of human α1AT augmentation therapy. Connective tissue breakdown after acute cigarette smoke exposure is mediated by PMNderived proteases and is prevented by α1AT. LPS-mediated lung injury is associated with both PMN serine elastases and collagenolytic proteases most likely derived from macrophages. A model of chronic LPS-mediated emphysema has been developed and is available for future studies of α1AT augmentation therapy.

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