Pro-inflammatory effects of substance P: new perspectives for the treatment of airway diseases?

Abstract

Non-adrenergic, non-cholinergic (i.e. NANC) neuronal transmission has been implicated in the pathophysiology of asthma. Attention has focused on both inhibitory NANC transmission mediated by its putative neurotransmitters vasoactive intestinal peptide (VIP) and nitric oxide (NO) and excitatory NANC transmission mediated by the sensory neuropeptides. Studies on rodent airway and non-airway tissue have demonstrated that activation of non-cholinergic excitatory nerves by mechanical or chemical stimuli can generate local axon reflexes that lead to bronchoconstriction and neurogenic inflammation. The sensory neuropeptides substance P (SP) and neurokinin A (NKA) have various effects that could contribute to changes observed in asthmatic airways, including smooth muscle contraction, submucosal gland secretion, vasodilatation, an increase in vascular permeability, stimulation of cholinergic nerves and stimulation of immune cells 1 Bertrand C. Geppetti P. Tachykinin and kinin receptor antagonists: therapeutic perspectives in allergic airway disease. Trends Pharmacol. Sci. 1996; 17: 255-259 Abstract Full Text PDF PubMed Scopus (81) Google Scholar , 2 Joos G.F. et al. Sensory neuropeptides and the human lower airways: present state and future directions. Eur. Respir. J. 1994; 7: 1161-1171 PubMed Google Scholar . Most of these effects have been observed in both human and animal tissue and are mediated by specific tachykinin receptors; stimulation of the NK2 receptor mediates a major part of the tachykinin-induced airway smooth muscle contraction, whereas stimulation of NK1 receptors induces vasodilatation, plasma protein extravasation, mucus secretion and stimulation of inflammatory and immune cells 3 Advenier C. et al. Role of tachykinins as contractile agonists of human airways in asthma. Clin. Exp. Allergy. 1999; 29: 579-584 Crossref PubMed Scopus (31) Google Scholar . The effects of tachykinins on the airways can be terminated by enzymatic degradation, mainly by the action of the ectoenzyme neutral endopeptidase 2 Joos G.F. et al. Sensory neuropeptides and the human lower airways: present state and future directions. Eur. Respir. J. 1994; 7: 1161-1171 PubMed Google Scholar . (2s-cis)-2-(diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-1-azabicyclo[2.2.2]octan-3-amine ((+)-(2s,3s)-3-methoxybenzyl amino)-2-phenylpiperidine N-[N2-[N-[N-[N-[2,3-didehydro-N-methyl-N-[N-[3-(2-pentylphenyl)-propionyl]-l-threonyl]tyrosyl-l-leucynyl]-d-phenylalanyl]-l-allothreonyl]-l-asparaginyl]-l-serine-n-lactone] N2-[(4r)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-l-prolyl]-N-phenylmethyl-3-(2-naphthyl)-l-alaninamide (s)-N-methyl-N[4-(4-acetylamino-4-phenyl piperidino)-2-(3,4-dichlorophenyl)butyl] benzamide