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A novel mechanism in the pathogenesis of Z α1-antitrypsin related emphysema
  1. J Goldring
  1. Specialist Registrar, Royal Free Hospital, London, UK;

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Alpha-1-antitrypsin (AT) is the predominant proteinase inhibitor in the lung. There are many abnormal variants of AT, and the Z form is one of the most frequently encountered. Z-AT is prone to polymerisation and the polymeric form aggregates in the liver, causing a plasma deficiency, while monomeric Z-AT is a less effective proteinase inhibitor than normal AT. This quantitative and functional deficiency exposes the lung to damaging proteinases such as neutrophil elastase which results in emphysema. The authors had previously shown that, in addition to localisation in hepatocytes, Z-AT polymers could be found in bronchoalveolar lavage (BAL) fluid and that, in vitro, these polymers attract neutrophils. They postulated that this neutrophil chemotaxis was another mechanism for the emphysema seen in Z-AT homozygotes. The present study was designed to assess the location of polymers in the lung and to test if chemotaxis occurs in vivo.

Tissue was harvested from lungs explanted from Z-AT and normal AT (M-AT) patients with emphysema. ELISA showed that 2.5-fold more AT was present in M-AT lungs than in Z-AT lungs and that polymers were only found in Z-AT lungs. Immunostaining showed that polymers and neutrophils were both present in the alveolar walls of Z-AT lungs. There was a 4-fold higher number of neutrophils in the Z-AT than the M-AT lungs. In a murine model, BAL fluid samples were taken after installation of polymeric Z-AT and M-AT into the lungs. Polymeric Z-AT produced a significant neutrophil influx into the BAL fluid compared with M-AT.

The findings of Z-AT polymer deposition in alveoli and their chemotactic properties in vivo establish a novel mechanism of emphysema pathogenesis in Z-AT homozygotes and might explain the progression of lung disease in these individuals despite replacement therapy.

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