Nociceptin Modulates Bronchoconstriction Induced by Sensory Nerve Activation in Mouse Lung.

Background: Nociceptin/orphanin FQ (N/OFQ) the endogenous ligand for the N/OFQ peptide receptor (NOP) inhibits tachykinin release in the airway of several animal models. The aim of this study was to investigate the role of N/OFQ-NOP receptor system in bronchoconstriction induced by sensory nerve activation in the isolated mouse lung. Materials and Methods: We used C57BL/6J NOP+/+, NOP-/- and Balb/C mice sensitised or not to ovalbumin. Bronchopulmonary function coupled with measurements of endogenous N/OFQ levels before and after capsaicin induced bronchoconstriction in presence or in absence of NOP selective agonists/ antagonists are presented. Results: N/OFQ significantly inhibited capsaicin induced bronchoconstriction in both naive and sensitized mice, these latter animals displaying airway hyperresponsiveness to capsaicin. The inhibitory effect of N/OFQ were not observed in NOP-/- mice and were mimicked/abolished by the selective NOP agonist/antagonist UFP-112/UFP-101 in NOP+/+ mice. UFP-101, alone potentiated the effect of capsaicin in naive but not in sensitized mice. Endogenous N/OFQ levels significantly decreased in sensitized with respect to naive mice. Conclusions: We have demonstrated that a reduction in endogenous N/OFQ or the lack of its receptor causes an increase in capsaicin induced bronchoconstriction implying a role for the N/OFQ-NOP receptor system in the modulation of capsaicin effects. Moreover, for the first time we documented differential airway responsiveness to capsaicin between naive and sensitized mice due, at least in part, to decreased endogenous N/OFQ levels in sensitized mice

Nociceptin Modulates Bronchoconstriction Induced by Sensory Nerve Activation in Mouse Lung

Background: Nociceptin/orphanin FQ (N/OFQ) the endogenous ligand for the N/OFQ peptide receptor (NOP) inhibits tachykinin release in the airway of several animal models. The aim of this study was to investigate the role of N/OFQ-NOP receptor system in bronchoconstriction induced by sensory nerve activation in the isolated mouse lung. Materials and Methods: We used C57BL/6J NOP+/+, NOP-/- and Balb/C mice sensitised or not to ovalbumin. Bronchopulmonary function coupled with measurements of endogenous N/OFQ levels before and after capsaicin induced bronchoconstriction in presence or in absence of NOP selective agonists/ antagonists are presented. Results: N/OFQ significantly inhibited capsaicin induced bronchoconstriction in both naive and sensitized mice, these latter animals displaying airway hyperresponsiveness to capsaicin. The inhibitory effect of N/OFQ were not observed in NOP-/- mice and were mimicked/abolished by the selective NOP agonist/antagonist UFP-112/UFP-101 in NOP+/+ mice. UFP-101, alone potentiated the effect of capsaicin in naive but not in sensitized mice. Endogenous N/OFQ levels significantly decreased in sensitized with respect to naive mice. Conclusions: We have demonstrated that a reduction in endogenous N/OFQ or the lack of its receptor causes an increase in capsaicin induced bronchoconstriction implying a role for the N/OFQ-NOP receptor system in the modulation of capsaicin effects. Moreover, for the first time we documented differential airway responsiveness to capsaicin between naive and sensitized mice due, at least in part, to decreased endogenous N/OFQ levels in sensitized mice

Sphingosine-1-phosphate/sphingosine kinase pathway is involved in mouse airway hyperresponsiveness.

Sphingosine-1-phosphate (S1P) has been shown to regulate numerous and diverse cell functions, including smooth muscle contraction. Here we assessed the role of S1P/Sphingosine kinase (SPK) pathway in the regulation of bronchial tone. Our objective was to determine, using an integrated pharmacologic and molecular approach, (1) the role of S1P as endogenous modulator of the bronchial tone, and (2) the linkage between S1P pathway and bronchial hyperresponsiveness. We evaluated S1P effects on isolated bronchi and whole lungs, harvested from Balb/c mice sensitized to ovalbumin (OVA) versus vehicle-treated mice, by measuring bronchial reactivity and lung resistance. We found that S1P administration on nonsensitized mouse bronchi does not cause any direct effect on bronchial tone, while a significant increase in Ach-induced contraction occurs after S1P challenge. Conversely, in OVA-sensitized mice S1P/SPK pathway triggers airway hyperesponsiveness. Indeed, S1P causes a dose-dependent contraction of isolated bronchi. Similarly, in the whole lung system S1P increased airway resistance only in OVA-sensitized mice. The action on bronchi of S1P is coupled to an enhanced expression of SPK(1) and SPK(2) as well as of S1P(2) and S1P(3) receptors. In these experiments the key role for S1P/SPK in hyperreactivity has been confirmed by pharmacologic modulation of SPKs. S1P/SPK pathway does not seem to play a major role in physiologic conditions, while it may become critical in pathologic conditions. These results open new windows for therapeutic strategies in diseases like asthma

Sphingosine-1-phosphate/sphingosine kinase pathway is involved in mouse airway hyperresponsiveness

Sphingosine-1-phosphate (S1P) has been shown to regulate numerous and diverse cell functions, including smooth muscle contraction. Here we assessed the role of S1P/Sphingosine kinase (SPK) pathway in the regulation of bronchial tone. Our objective was to determine, using an integrated pharmacologic and molecular approach, (1) the role of S1P as endogenous modulator of the bronchial tone, and (2) the linkage between S1P pathway and bronchial hyperresponsiveness. We evaluated S1P effects on isolated bronchi and whole lungs, harvested from Balb/c mice sensitized to ovalbumin (OVA) versus vehicle-treated mice, by measuring bronchial reactivity and lung resistance. We found that S1P administration on nonsensitized mouse bronchi does not cause any direct effect on bronchial tone, while a significant increase in Ach-induced contraction occurs after S1P challenge. Conversely, in OVA-sensitized mice S1P/ SPK pathway triggers airway hyperesponsiveness. Indeed, S1P causes a dose-dependent contraction of isolated bronchi. Similarly, in the whole lung system S1P increased airway resistance only in OVA-sensitized mice. The action on bronchi of S1P is coupled to an enhanced expression of SPK1 and SPK2 as well as of S1P2 and S1P3 receptors. In these experiments the key role for S1P/SPK in hyperreactivity has been confirmed by pharmacologic modulation of SPKs. S1P/SPK pathway does not seem to play a major role in physiologic conditions, while it may become critical in pathologic conditions. These results open new windows for therapeutic strategies in diseases like asthma

Systemic Administration of Sphingosine-1-phosphate Increases Bronchial Hyper-Responsiveness in the Mouse

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that plays important roles in allergic responses, including asthma. S1P acts on many cell types, such as mast cells, the airway epithelium, airway smooth muscle, and many immune cells. In this study we have evaluated whether a systemic administration of S1P to Balb/c mice modifies airway reactivity. Our data show that S1P (0.1-10 ng) given subcutaneously to Balb/c mice causes a specific and dose-dependent increase in cholinergic reactivity of bronchial tissues in vitro. This effect is (1) dose dependent, with a maximal effect of the dose of 10 ng of S1P; and (2) time dependent, reaching a maximal effect 21 days after S1P administration. Similarly, in the whole lung assay there is a dose- and time-dependent increase in lung resistance. Lungs isolated from S1P-treated mice displayed an increase in mast cell number. Furthermore, there is an increase of IL-4, IL-13, and IL-17 production. In conclusion, our data demonstrate that S1P signaling is involved in the complex pathway underlying airway hyperresponsiveness

Autophagy acts as a safeguard mechanism against G-quadruplex ligand-mediated DNA damage

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