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Published ahead of print on January 14, 2005, doi:10.1165/rcmb.2004-0321OC

Am. J. Respir. Cell Mol. Biol., Volume 32, Number 4, April 2005, 334-341

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Submitted on October 8, 2004
Revised on January 13, 2005

Induction of human airway smooth muscle apoptosis by neutrophils and neutrophil elastase

Ute Oltmanns1, Maria B Sukkar1, Shaoping Xie1, Matthias John2, and Kian Fan Chung1*

1 Department of Thoracic Medicine, National Heart and Lung Institution, London, United Kingdom, 2 Department of Pneumology, Charite University Hospital, Berlin, Germany

* To whom correspondence should be addressed. E-mail: f.chung{at}imperial.ac.uk.

Neutrophils are an important component of airway inflammation and may interact with human airway smooth muscle cells (HASMC). We investigated the effect of neutrophils and of neutrophil-derived proteases on HASMC survival. When coincubated with neutrophils (0.1-1x106 cells/ml), attachment of human ASMC was reduced to 12.3 ± 4.3% compared to untreated controls after 72 hours. HASMC showed nuclear condensation and fragmentation (41.6 ± 8.1% compared to baseline of 3.1 ± 0.4%), and the biochemical markers of apoptosis, annexin V-binding (9.7 ± 0.7%; baseline 1.1 ± 0.3%) and cleaved caspase-3 expression, were observed. The proteolytic activity released by neutrophils was essential for the pro-apoptotic effect because inhibition of elastase activity by {alpha}1-antitrypsin and MeOSuc-Ala-Ala-Pro-Ala-CMK (MSACK) reduced HASMC apoptosis. Human neutrophil elastase (0.1-3µg/ml) induced apoptosis of HASMC, as well as other neutrophil serine proteases, cathepsin G and proteinase 3. Fibronectin degradation products were present in HASMC supernatants exposed to neutrophil-conditioned media and to neutrophil elastase. The local release of proteases from neutrophils present in airway smooth muscle cells may lead to HASMC apoptosis as a result of matrix degradation and loss of cell attachment. This may limit pathological changes such as ASMC hyperplasiaand ECM deposition seen in airway remodeling.




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