Cationic protein-induced sensory nerve activation: role of substance P in airway hyperresponsiveness and plasma protein extravasation.
We have previously reported that human eosinophil granule major basic protein and synthetic cationic proteins such as poly-L-arginine and poly-L-lysine, can increase airway responsiveness in vivo. In the present study, we have investigated whether activation of sensory C-fibers is important in this phenomenon. Dose-response curves to methacholine were constructed before and 1 h after intratracheal instillation of poly-L-lysine in anaesthetized spontaneously breathing rats, and the concentration of methacholine required to induce a doubling in total lung resistance was calculated. Poly-L-lysine induced a fivefold increase in airway responsiveness, which was inhibited by neonatal capsaicin treatment and potentiated by phosphoramidon (100 micrograms/ml). Furthermore, pretreatment with either CP, 96-345, or RP-67580 two selective NK-1 receptor antagonists inhibited poly-L-lysine-induced airway hyperresponsiveness and plasma protein extravasation. In vitro, cationic proteins stimulated the release of calcitonin gene-related peptide-like immunoreactivity from perfused slices of the main bronchi. Our results demonstrate that cationic proteins can activate sensory C-fibers in the airways, an effect which is important in the subsequent development of airway hyperresponsiveness and plasma protein extravasation. Cationic proteins may therefore function as a link between inflammatory cell accumulation and sensory nerve activation.
Coyle
A J
AJ
Department of Medicine, University of Colorado Health Science Center, Denver.
Perretti
F
F
Manzini
S
S
Irvin
C G
CG
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D001980:Bronchi / Q000187:drug effects / Q000294:innervation / Q000502:physiology*; D015740:Calcitonin Gene-Related Peptide / Q000032:analysis; D002199:Capillary Permeability / Q000502:physiology; D002211:Capsaicin / Q000494:pharmacology; D002412:Cations / Q000494:pharmacology; D005260:Female; D006020:Glycopeptides / Q000494:pharmacology; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology*; D011107:Polylysine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013373:Substance P / Q000502:physiology*
D001798:Blood Proteins; D002412:Cations; D006020:Glycopeptides; D064729:Neurokinin-1 Receptor Antagonists; D010455:Peptides; D016210:Methacholine Chloride; D011107:Polylysine; C015462:polyarginine; D013373:Substance P; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin; C008890:phosphoramidon