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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online May 21, 2002 as doi:10.1096/fj.01-0939fje. |
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Division d’Hypertension and
Division de Dermatologie, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland;
Hôpitaux Universitaires de Genève, Laboratoire de Rhinologie Experimentale/Clinique et Policlinique d’Oto-Rhino-Laryngologie et Chirurgie Cervico-Faciale, 1211 Genève, Switzerland;
Department of Pharmacology, Mount Sinai School of Medicine, New York, New York, USA;
* Hôpitaux Universitaires de Genève, Département de Pathologie Clinique, 1211 Genève, Switzerland; and
Hôpitaux Universitaires de Genève, Divisions d’Investigations Anesthesiologiques, 1211 Genève, Switzerland.
2Correspondence: E-mail: Eric.Grouzmann{at}chuv.hospvd.ch
SPECIFIC AIMS
The nasal mucosa is densely innervated by sensory nerve fibers that release substance P (SP) during neurogenic inflammation, contributing to the development of chronic rhinosinusitis, a common debilitating respiratory disease. SP is sequentially cleaved by the specific serine exopeptidase named dipeptidylpeptidase IV (DPPIV) or CD26 into SP3–11 and SP5–11. The aim of this study was to establish the role of DPPIV in the regulation of SP-induced neurogenic inflammation in human and animal models.
PRINCIPAL FINDINGS
1. DPPIV activity and inflammation are correlated in human nasal mucosa
DPPIV immunoreactivity was detected in submucosal seromucous glands of the human nasal mucosa, leukocytes, and endothelial cells in blood vessels. Nasal mucosa biopsies were obtained in both nostrils in 45 patients suffering from chronic rhinosinusitis secondary to anatomical deformity of the nasal septum and the middle turbinate resulting in persistent mechanical stimulation. Histological analysis revealed marked differences in the density of inflammatory cells within the submucosa of the nasal biopsies studied (Fig. 1
A.). The density of inflammatory cells was plotted against DPPIV activity. We found variations in nasal mucosa DPPIV activity ranging from undetectable to 707 pmol/(min·mg) (Fig. 1B
). A low activity of DPPIV was associated with high density of inflammatory cells. The regressive correlation was statistically significant (P<0.001) (Fig. 1B
.). The density of inflammatory cells in each biopsy was plotted against the subjective evaluation of nasal obstruction. These data fitted a statistically significant correlation (P<0.01), suggesting that nasal inflammation increased in parallel with subjective severity of nasal symptoms.
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Six months after endonasal surgery, nasal mucosa biopsies were obtained from 10 patients with significant improvement of their symptoms. The DPPIV activity was significantly increased in all the samples studied compared with the preoperative state (P<0.001), indicating that DPPIV activity can be restored in parallel with satisfactory nasal function.
2. DPPIV activity modulates the vasodilatory response mediated by SP
An animal model was developed to study the involvement of DPPIV in rhinitis. In the nasal mucosa of anesthetized pigs, repeated injections of high doses of exogenous SP caused similar increases of blood flow in the sphenopalatine artery, the main arterial blood supply to the nasal mucosa. These reproducible decreases in sphenopalatine vascular resistance (SVR, derived from mean arterial blood pressure and blood flow in the sphenopalatine artery) evoked by SP indicated that desensitization of neurokinin (NK) receptors did not occur. Therefore, we performed experiments to obtain a dose-response curve with SP (0.001–100 ng) and assessed the duration of the vasodilatation and the area under the curve (AUC) on SVR. Reproducible dose-response curves were obtained over 45 min with six doses of SP. The vasodilatation ranged between 15.1% ± 3.3% and 37.3% ± 3.3% after local intra-arterial administration of 0.001 and 100 ng of SP, respectively. The duration of the SVR reduction as well as the AUC induced by exogenous SP were dose dependent. We assessed whether the vasodilatation evoked by SP was affected by a pretreatment with recombinant DPPIV (rDPPIV). Two doses of SP (0.1 and 1 ng) were administered, resulting in 13.1 and 14.9% reduction in SVR, respectively. The same animals received 50 µg (530 pmol) of rDPPIV and similar doses of SP were injected. Recombinant DPPIV had no vascular effect per se. Subsequent administration of SP resulted in a dramatic attenuation of the SP-evoked vasodilatory response by 66 and 71%, respectively, compared with control (Fig. 2
).
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Since DPPIV cleaves SP into SP5–11, we examined whether SP5–11 was capable of decreasing SVR. Similar to our observation with SP, a dose-response curve was obtained with 0.01 ng to 1000 ng of SP5–11 and a 5- 35% decrease in SVR was observed, respectively. However, the vasodilatory effect of SP5–11 was considerably lower than that of SP. It was not possible to calculate the exact ED50 for SP and SP5–11 since administration of higher doses of SP evoked lethal systemic vasodilatation. Based on molarity, SP is an 
100- to 1000-fold more potent vasodilator than SP5–11. Therefore, rDPPIV administration to the pigs probably results in an almost immediate conversion to SP5–11 that behaves as a very weak neurokinin agonist.
We administered 0.1 mg (31.3 nmol/kg) of the aminoacylpyrrolidine-2-nitrile Ala-Pyrr-2-CN, a specific, long-acting, and potent (Ki at 0.2 µM) inhibitor of DPPIV to establish a putative role of endogenous DPPIV to maintain nasal vascular tone or/and to enhance the effect of exogenous administration of SP. The inhibitor had no effect per se on SVR. When 0.2 mg of the DPPIV inhibitor was injected, again there was no effect, but this dose markedly increased by 41% the vasodilatory effect of a low dose of SP (0.001 ng). To further characterize the nature of the neurokinin receptor subtype involved in the reduction of SVR, pigs were pretreated with a NK1 antagonist, L-733060, at 114 nmol/kg to evaluate the blockade of SP-induced decrease in SVR. We found a clear inhibition of the SP effect at all but the highest dose of SP (100 ng). Accordingly, the SP effect on SVR is likely to be mediated through the NK1 receptor.
CONCLUSION
We have shown that the activity of the enzyme DPPIV involved in the degradation of the sensory and proinflammatory neuropeptide SP is markedly reduced in the nasal mucosa of rhinitic patients. The activity of DPPIV is significantly increased in nasal mucosa after treatment and symptom improvement. To support our observations in humans, we performed in vivo experiments in pigs and showed that pretreatment with recombinant DPPIV dramatically reduces nasal vasodilatation evoked by SP.
The fact that the enzyme activity rose after treatment of chronic rhinosinusitis favors the involvement of the enzyme in this pathology. An increase of sensory neuropeptide activity is associated with an augmentation of the local vasodilatation, plasma exudation and influx of inflammatory cells. This neurogenic inflammation could increase the intensity of the nasal symptoms in patients with chronic rhinosinusitis. The main nonadrenergic and noncholinergic mediators released by sensory nerves in the nasal mucosa during neurogenic inflammation are SP and CGRP. For instance, histamine, capsaicin, and bradykinin induce SP release from primary sensory-C fibers.
SP induces dose-dependent vasodilatation of nasal resistance and capacitance vessels in cats, pigs, and human nasal mucosa. SP most likely stimulates histamine release from mast cells and potentiates histamine action. In this reaction, SP mediates the increase in vein permeability, resulting in nonadrenergic noncholinergic vasodilatation of the nasal vascular bed and an increased vascular permeability to plasma protein presumably via NK1 receptors.
Pretreatment with rDPPIV significantly decreased peak and duration of the vasodilatation evoked by SP. The reduction of SP degradation could contribute to maintain nasal mucosa inflammation since allergic patients have higher baseline levels of SP immunoreactivity in nasal lavage fluids than nonallergic controls. Other substrates such as interleukin1ß (IL-1ß), IL-2, IL-5, IL-6, IL-10, IL-13, tumor necrosis factor ß, and monocyte chemotactic protein I are targets for DPPIV and might be involved in inflammation process observed during DPPIV deficiency. Nevertheless, none of these mediators have proved to have a direct vascular effect when applied in nasal mucosa, and no evidence has demonstrated that these cytokines are indeed cleaved in vitro by DPPIV.
Some proteases have already been shown to be implicated in the metabolism of biologically active peptides in various tissues. The inhibition of neutral endopeptidase (NEP) or angiotensin-converting enzyme (ACE) activity by phosphoramidon or captopril, respectively, enhances the vasodilatory effects of SP in various species, including humans. These observations support the hypothesis that reduced NEP activity and concomitant increase in SP concentrations contribute to the intensity of symptoms and mucosal inflammation in nonallergic chronic rhinosinusitis. We have discovered that DPPIV is another enzyme involved in neuropeptide catabolism, resulting in a complex regulation of the different pathophysiological pathways leading to chronic rhinosinusitis (Fig. 3
).
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Several drugs have been developed to reduce the intensity of rhinosinusitis symptoms based on inhibition of inflammatory mediators. The present data suggest that normal upper airway homeostasis is dependent on normal DPPIV activity. Several aspects regarding the dysfunction of DPPIV activity in relation to chronic inflammatory diseases remain to be clarified.
FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.01-0939fje; to cite this article, use FASEB J. (May 21, 2002) 10.1096/fj.01-0939fje. 
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