title: Induction of human airway smooth muscle apoptosis by neutrophils and neutrophil elastase.
abstract: 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 co-incubated with neutrophils (0.1-1 x 10(6) cells/ml), attachment of human ASMC was reduced to 12.3 +/- 4.3% compared with untreated controls after 72 h. HASMC showed nuclear condensation and fragmentation (41.6 +/- 8.1% compared with 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 proapoptotic effect because inhibition of elastase activity by alpha(1)-antitrypsin and MeOSuc-Ala-Ala-Pro-Ala-CMK (MSACK) reduced HASMC apoptosis. Human neutrophil elastase (0.1-3 microg/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 pathologic changes such as ASMC hyperplasia and extracellular matrix deposition seen in airway remodeling.
authors.affiliation: Thoracic Medicne, National Heart & Lung Institute, Imperial College, Dovehouse St., London SW3 6LY, UK.
authors.forename: Ute
authors.initials: U
authors.lastname: Oltmanns
authors.forename: Maria B
authors.initials: MB
authors.lastname: Sukkar
authors.forename: Shaoping
authors.initials: S
authors.lastname: Xie
authors.forename: Matthias
authors.initials: M
authors.lastname: John
authors.forename: K Fan
authors.initials: KF
authors.lastname: Chung
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D009130:Muscle, Smooth / Q000166:cytology* / Q000187:drug effects; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D012137:Respiratory System / Q000166:cytology* / Q000187:drug effects; D015843:Serpins / Q000494:pharmacology
chemical_list: D015843:Serpins; D019272:Leukocyte Elastase; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases