Contribution of sensory nerves to LPS-induced hyperresponsiveness of human isolated bronchi.
OBJECTIVE
Bacterial lipopolysaccharide (LPS) can induce bronchial hyperresponsiveness (BHR), but the underlying mechanisms remain to be determined. Here, the possible contribution of sensory nerves to LPS-induced BHR was examined in human isolated bronchi to pharmacologically identify the mechanisms underlying this phenomenon.


METHODS
Human isolated bronchial tone was induced by electrical field stimulation (EFS). The responses of airways to LPS, with or without capsaicin desensitization or thiorphan treatment were studied and the transient receptor potential vanilloid type 1 (TRPV1) expression was assessed. We performed similar experiments in the presence of a TRPV1 or a neurokinin (NK) 2 receptor antagonist using SB366791 and GR159897, respectively.


RESULTS
LPS increased (≃2.3-fold, P<0.001) the contraction induced by EFS, compared to control tissues. Acute administration of capsaicin enhanced (≃2.3-fold, P<0.001) the EFS-mediated contraction, but did not potentiate the effect of LPS. Thiorphan increased (≃1.3-fold, P<0.05) the contractile response of LPS treated tissues and, at lower frequencies, it enhanced (≃1.7-fold, P<0.001) the capsaicin-induced contraction. In capsaicin-desensitized bronchi, LPS did not modify (P>0.05) the EFS contractile response, nor after treatment with thiorphan. Capsaicin desensitization reduced (≃0.4-fold, P<0.001) the LPS-induced BHR. SB366791 and GR159897 prevented the LPS-induced BHR and the release of NKA. LPS increased (+85.3±9.5%, P<0.01) the surface membrane expression of TRPV1 in parasympathetic ganglia.


CONCLUSIONS
Our results demonstrate the involvement of capsaicin-sensitive sensory nerves and neutral endopeptidases in LPS-induced BHR of the human bronchi, associated with an upregulation of TRPV1 and release of NKA.
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
Luigino
L
Calzetta
Unit of Pharmacology, Department of Experimental Medicine, Second University of Naples, Naples, Italy.
Livio
L
Luongo
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy. Electronic address: mario.cazzola@uniroma2.it.
Mario
M
Cazzola
The Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, UK.
Clive
C
Page
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
Paola
P
Rogliani
Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy.
Francesco
F
Facciolo
Unit of Pharmacology, Department of Experimental Medicine, Second University of Naples, Naples, Italy.
Sabatino
S
Maione
Unit of Pharmacology, Department of Experimental Medicine, Second University of Naples, Naples, Italy.
Annalisa
A
Capuano
Unit of Pharmacology, Department of Experimental Medicine, Second University of Naples, Naples, Italy.
Barbara
B
Rinaldi
Unit of Pharmacology, Department of Experimental Medicine, Second University of Naples, Naples, Italy.
Maria Gabriella
MG
Matera
D000813:Anilides / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000503:physiopathology*; D002211:Capsaicin / Q000494:pharmacology*; D002934:Cinnamates / Q000494:pharmacology; D004558:Electric Stimulation; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D015260:Neprilysin / Q000378:metabolism; D015288:Neurokinin A / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011984:Sensory Receptor Cells / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000235:genetics; D015854:Up-Regulation
D000813:Anilides; D002934:Cinnamates; C092990:GR 159897; D007211:Indoles; D008070:Lipopolysaccharides; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; D010880:Piperidines; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D015288:Neurokinin A; D015260:Neprilysin; D002211:Capsaicin
BHR; Human isolated bronchi; LPS; NK(2) receptor; NKA; Sensory nerves; TRPV1