Replication-deficient adenoviral vector for gene transfer potentiates airway neurogenic inflammation.
Human trials for the treatment of cystic fibrosis lung disease with adenoviral vectors have been complicated by acute inflammatory reactions of unknown etiology. Because replicating respiratory viruses can potentiate tachykinin-mediated neurogenic inflammatory responses in airways, we studied whether the endotracheal administration of a replication-deficient adenoviral vector potentiated this response. The vector Ad5CMVLacZ was administered endotracheally to rats and the leakage of Evans blue dye was used to measure the capsaicin-induced neurogenic albumin extravasation. These studies show that neurogenic albumin extravasation is significantly potentiated in the airways of rats after administration of Ad5CMVLacZ. This inflammatory response can be blocked by selective antagonists of the substance P receptor or by glucocorticoids. Therefore, (1) the acute airway inflammation observed in patients after exposure to adenoviral vectors may exhibit a neurogenic component, which can be blocked pharmacologically, and (2) preclinical adenoviral vector safety studies of other organs innervated by the tachykinin system, e.g., coronary arteries and gastrointestinal tract, should include assessment of neurogenic inflammation.
Piedimonte
G
G
Department of Pediatrics, University of Miami School of Medicine, Florida, USA.
Pickles
R J
RJ
Lehmann
J R
JR
McCarty
D
D
Costa
D L
DL
Boucher
R C
RC
D000260:Adenoviruses, Human / Q000235:genetics* / Q000528:radiation effects; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D005363:Ficusin; D018014:Gene Transfer Techniques / Q000009:adverse effects*; D005822:Genetic Vectors / Q000009:adverse effects* / Q000528:radiation effects; D005938:Glucocorticoids / Q000494:pharmacology; D006358:Hot Temperature; D007249:Inflammation; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D009475:Neurons, Afferent; D017319:Photosensitizing Agents; D010880:Piperidines / Q000494:pharmacology; D011489:Protein Denaturation; D051381:Rats; D011916:Rats, Inbred F344; D018040:Receptors, Neurokinin-1 / Q000502:physiology; D012137:Respiratory System / Q000294:innervation* / Q000503:physiopathology; D013373:Substance P / Q000378:metabolism / Q000494:pharmacology; D014466:Ultraviolet Rays
D005938:Glucocorticoids; D064729:Neurokinin-1 Receptor Antagonists; D017319:Photosensitizing Agents; D010880:Piperidines; D018040:Receptors, Neurokinin-1; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D013373:Substance P; D003907:Dexamethasone; D005363:Ficusin; D002211:Capsaicin