Adenoviral augmentation of elafin protects the lung against acute injury mediated by activated neutrophils and bacterial infection.
During acute pulmonary infection, tissue injury may be secondary to the effects of bacterial products or to the effects of the host inflammatory response. An attractive strategy for tissue protection in this setting would combine antimicrobial activity with inhibition of human neutrophil elastase (HNE), a key effector of neutrophil-mediated tissue injury. We postulated that genetic augmentation of elafin (an endogenous inhibitor of HNE with intrinsic antimicrobial activity) could protect the lung against acute inflammatory injury without detriment to host defense. A replication-deficient adenovirus encoding elafin cDNA significantly protected A549 cells against the injurious effects of both HNE and whole activated human neutrophils in vitro. Intratracheal replication-deficient adenovirus encoding elafin cDNA significantly protected murine lungs against injury mediated by Pseudomonas aeruginosa in vivo. Genetic augmentation of elafin therefore has the capacity to protect the lung against the injurious effects of both bacterial pathogens resistant to conventional antibiotics and activated neutrophils.
Simpson
A J
AJ
Rayne Laboratory, Respiratory Medicine Unit, Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh EH8 9AG, Scotland, United Kingdom.
Wallace
W A
WA
Marsden
M E
ME
Govan
J R
JR
Porteous
D J
DJ
Haslett
C
C
Sallenave
J M
JM
D000208:Acute Disease; D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000235:genetics* / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D002452:Cell Count; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D007442:Intubation, Intratracheal; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000633:toxicity; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018375:Neutrophil Activation / Q000276:immunology*; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D011552:Pseudomonas Infections / Q000201:enzymology / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*; D011550:Pseudomonas aeruginosa / Q000276:immunology; D014162:Transfection; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D019272:Leukocyte Elastase