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Mirra D, Esposito R, Spaziano G, Rafaniello C, Panico F, Squillante A, Falciani M, Abrego-Guandique DM, Caiazzo E, Gallelli L, Cione E, D’Agostino B. miRNA Signatures in Alveolar Macrophages Related to Cigarette Smoke: Assessment and Bioinformatics Analysis. Int J Mol Sci 2025; 26:1277. [PMID: 39941045 PMCID: PMC11818525 DOI: 10.3390/ijms26031277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/23/2025] [Accepted: 01/30/2025] [Indexed: 02/16/2025] Open
Abstract
Cigarette smoke (CS) is a driver of many respiratory diseases, including chronic obstructive pulmonary disease (COPD) and non-small cell lung cancer (NSCLC). Tobacco causes oxidative stress, impaired phagocytosis of alveolar macrophages (AMs), and alterations in gene expression in the lungs of smokers. MicroRNAs (miRNAs) are small non-coding RNAs that influence several regulatory pathways. Previously, we monitored the expressions of hsa-miR-223-5p, 16-5p, 20a-5p, -17-5p, 34a-5p, and 106a-5p in AMs derived from the bronchoalveolar lavage (BAL) of subjects with NSCLC, COPD, and smoker and non-smoker control groups. Here, we investigated the capability of CS conditionate media to modulate the abovementioned miRNAs in primary AMs obtained in the same 43 sex-matched subjects. The expressions of has-miR-34a-5p, 17-5p, 16-5p, 106a-5p, 223-5p, and 20a-5p were assessed before and after in vitro CS exposure by RT-PCR. In addition, a comprehensive bioinformatic analysis of miRNAs KEGGS and PPI linked to inflammation was performed. Distinct and common miRNA expression profiles were identified in response to CS, suggesting their possible role in smoking-related diseases. It is worth noting that, following exposure to CS, the expression levels of hsa-miR-34a-5p and 17-5p in both smokers and non-smokers, 106a-5p in non-smokers, and 20a-5p in smokers, shifted towards those found in individuals with COPD, suggesting them as a risk factor in developing this lung condition. Moreover, CS-focused sub-analysis identified miRNA which exhibited CS-dependent pattern and modulated mRNA involved in the immune system or AMs property regulation. In conclusion, our study uncovered miRNA signatures in AMs exposed to CS, indicating that CS might modify epigenetic patterns that contribute to macrophage activation and lung disease onset and progression.
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Affiliation(s)
- Davida Mirra
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (D.M.); (R.E.); (E.C.); (B.D.)
| | - Renata Esposito
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (D.M.); (R.E.); (E.C.); (B.D.)
| | - Giuseppe Spaziano
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (D.M.); (R.E.); (E.C.); (B.D.)
| | - Concetta Rafaniello
- Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, 80138 Naples, Italy;
- Section of Pharmacology “L. Donatelli”, Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
| | - Francesca Panico
- Science of Health Department, School of Medicine, University of Catanzaro, 88100 Catanzaro, Italy; (F.P.); (D.M.A.-G.)
| | | | - Maddalena Falciani
- Pulmonary and Critical Care Medicine, Ospedale Scarlato, 84018 Scafati, Italy;
| | | | - Eleonora Caiazzo
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (D.M.); (R.E.); (E.C.); (B.D.)
| | - Luca Gallelli
- Clinical Pharmacology and Pharmacovigilance Unit, Department of Health Sciences, Mater Domini Hospital, University of “Magna Graecia”, 88100 Catanzaro, Italy;
| | - Erika Cione
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy;
| | - Bruno D’Agostino
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (D.M.); (R.E.); (E.C.); (B.D.)
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Mirra D, Esposito R, Spaziano G, Sportiello L, Panico F, Squillante A, Falciani M, Cerqua I, Gallelli L, Cione E, D’Agostino B. MicroRNA Monitoring in Human Alveolar Macrophages from Patients with Smoking-Related Lung Diseases: A Preliminary Study. Biomedicines 2024; 12:1050. [PMID: 38791013 PMCID: PMC11118114 DOI: 10.3390/biomedicines12051050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 04/18/2024] [Accepted: 05/01/2024] [Indexed: 05/26/2024] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a progressive lung disease that is commonly considered to be a potent driver of non-small cell lung cancer (NSCLC) development and related mortality. A growing body of evidence supports a role of the immune system, mainly played by alveolar macrophages (AMs), in key axes regulating the development of COPD or NSCLC phenotypes in response to harmful agents. MicroRNAs (miRNAs) are small non-coding RNAs that influence most biological processes and interfere with several regulatory pathways. The purpose of this study was to assess miRNA expression patterns in patients with COPD, NSCLC, and ever- or never-smoker controls to explore their involvement in smoking-related diseases. Bronchoalveolar lavage (BAL) specimens were collected from a prospective cohort of 43 sex-matched subjects to determine the expressions of hsa-miR-223-5p, 16-5p, 20a-5p, -17-5p, 34a-5p and 106a-5p by RT-PCR. In addition, a bioinformatic analysis of miRNA target genes linked to cancer was performed. Distinct and common miRNA expression levels were identified in each pathological group, suggesting their possible role as an index of NSCLC or COPD microenvironment. Moreover, we identified miRNA targets linked to carcinogenesis using in silico analysis. In conclusion, this study identified miRNA signatures in AMs, allowing us to understand the molecular mechanisms underlying smoking-related conditions and potentially providing new insights for diagnosis or pharmacological treatment.
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Affiliation(s)
- Davida Mirra
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (D.M.); (R.E.); (B.D.)
| | - Renata Esposito
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (D.M.); (R.E.); (B.D.)
| | - Giuseppe Spaziano
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (D.M.); (R.E.); (B.D.)
| | - Liberata Sportiello
- Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, 80138 Naples, Italy;
- Department of Experimental Medicine-Section of Pharmacology “L. Donatelli”, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
| | - Francesca Panico
- Department of Health Sciences, University of “Magna Graecia”, 88100 Catanzaro, Italy; (F.P.); (L.G.)
| | | | - Maddalena Falciani
- Pulmonary and Critical Care Medicine, Ospedale Scarlato, 84018 Scafati, Italy;
| | - Ida Cerqua
- Department of Pharmacy, University Federico II of Naples, Via D. Montesano 49, 80131 Naples, Italy;
| | - Luca Gallelli
- Department of Health Sciences, University of “Magna Graecia”, 88100 Catanzaro, Italy; (F.P.); (L.G.)
| | - Erika Cione
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy;
| | - Bruno D’Agostino
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (D.M.); (R.E.); (B.D.)
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Mirra D, Esposito R, Spaziano G, Rafaniello C, Iovino P, Cione E, Gallelli L, D'Agostino B. Association between Sex-Related ALOX5 Gene Polymorphisms and Lung Atopy Risk. J Clin Med 2023; 12:jcm12082775. [PMID: 37109111 PMCID: PMC10145460 DOI: 10.3390/jcm12082775] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 03/29/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
Atopy is an exaggerated IgE-mediated immune response to foreign antigens in which metabolic abnormalities of the leukotrienes (LTs) pathway play a crucial role. Recent studies have described sex as a key variable in LT biosynthesis, partly explaining why treatment with anti-LT drugs in atopic subjects leads to better control of symptoms in women. In addition, variability in LT production is often associated with single nucleotide polymorphisms (SNPs) in the arachidonate 5-lipoxygenase (ALOX5) gene, which encodes the leukotriene-synthesizing enzyme machinery, 5-lipoxygenase (5-LO). This study aimed to investigate whether two SNPs of ALOX5 are implicated in sex differences in allergic diseases in a prospective cohort of 150 age- and sex-matched atopic and healthy subjects. Rs2029253 and rs2115819 were genotyped using allele-specific RT-PCR, and serum levels of 5-LO and LTB4 were measured by ELISA. Both polymorphisms are significantly more common in women than in men, and their influences on LT production vary as a function of sex, leading to a decrease in men's and an increase in women's serum levels of 5-LO and LTB4. These data represent a new resource for understanding sex-related differences in lung inflammatory diseases, partly explaining why women are more likely to develop allergic disorders than men.
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Affiliation(s)
- Davida Mirra
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", 81100 Caserta, Italy
| | - Renata Esposito
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", 81100 Caserta, Italy
| | - Giuseppe Spaziano
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", 81100 Caserta, Italy
| | - Concetta Rafaniello
- Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, 80138 Naples, Italy
- Department of Experimental Medicine, Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Pasquale Iovino
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", 81100 Caserta, Italy
| | - Erika Cione
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
| | - Luca Gallelli
- Clinical Pharmacology and Pharmacovigilance Unit, Department of Health Sciences, Mater Domini Hospital, University of Catanzaro, 88100 Catanzaro, Italy
| | - Bruno D'Agostino
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", 81100 Caserta, Italy
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Lung microRNAs Expression in Lung Cancer and COPD: A Preliminary Study. Biomedicines 2023; 11:biomedicines11030736. [PMID: 36979715 PMCID: PMC10045129 DOI: 10.3390/biomedicines11030736] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/21/2023] [Accepted: 02/24/2023] [Indexed: 03/05/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) is one of the deadliest diseases worldwide and represents an impending burden on the healthcare system. Despite increasing attention, the mechanisms underlying tumorigenesis in cancer-related diseases such as COPD remain unclear, making novel biomarkers necessary to improve lung cancer early diagnosis. MicroRNAs (miRNAs) are short non-coding RNA that interfere with several pathways and can act as oncogenes or tumor suppressors. This study aimed to compare miRNA lung expression between subjects with NSCLC and COPD and healthy controls to obtain the miRNA expression profile by analyzing shared pathways. Lung specimens were collected from a prospective cohort of 21 sex-matched subjects to determine the tissue miRNA expression of hsa-miR-34a-5p, 33a-5p, 149-3p, 197-3p, 199-5p, and 320a-3p by RT-PCR. In addition, an in silico prediction of miRNA target genes linked to cancer was performed. We found a specific trend for has-miR-149-3p, 197-3p, and 34a-5p in NSCLC, suggesting their possible role as an index of the tumor microenvironment. Moreover, we identified novel miRNA targets, such as the Cyclin-Dependent Kinase (CDK) family, linked to carcinogenesis by in silico analysis. In conclusion. this study identified lung miRNA signatures related to the tumorigenic microenvironment, suggesting their possible role in improving the evaluation of lung cancer onset.
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Esposito R, Mirra D, Sportiello L, Spaziano G, D’Agostino B. Overview of Antiviral Drug Therapy for COVID-19: Where Do We Stand? Biomedicines 2022; 10:2815. [PMID: 36359334 PMCID: PMC9687182 DOI: 10.3390/biomedicines10112815] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 10/31/2022] [Accepted: 11/02/2022] [Indexed: 09/08/2024] Open
Abstract
The vaccine weapon has resulted in being essential in fighting the COVID-19 outbreak, but it is not fully preventing infection due to an alarming spreading of several identified variants of concern. In fact, the recent emergence of variants has pointed out how the SARS-CoV-2 pandemic still represents a global health threat. Moreover, oral antivirals also develop resistance, supporting the need to find new targets as therapeutic tools. However, cocktail therapy is useful to reduce drug resistance and maximize vaccination efficacy. Natural products and metal-drug-based treatments have also shown interesting antiviral activity, representing a valid contribution to counter COVID-19 outbreak. This report summarizes the available evidence which supports the use of approved drugs and further focuses on significant clinical trials that have investigated the safety and efficacy of repurposing drugs and new molecules in different COVID-19 phenotypes. To date, there are many individuals vulnerable to COVID-19 exhibiting severe symptoms, thus characterizing valid therapeutic strategies for better management of the disease is still a challenge.
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Affiliation(s)
- Renata Esposito
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy
| | - Davida Mirra
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy
| | - Liberata Sportiello
- Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, 80138 Naples, Italy
- Department of Experimental Medicine—Section of Pharmacology “L. Donatelli”, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
| | - Giuseppe Spaziano
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy
| | - Bruno D’Agostino
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy
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Mirra D, Cione E, Spaziano G, Esposito R, Sorgenti M, Granato E, Cerqua I, Muraca L, Iovino P, Gallelli L, D’Agostino B. Circulating MicroRNAs Expression Profile in Lung Inflammation: A Preliminary Study. J Clin Med 2022; 11:jcm11185446. [PMID: 36143090 PMCID: PMC9500709 DOI: 10.3390/jcm11185446] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/08/2022] [Accepted: 09/12/2022] [Indexed: 11/29/2022] Open
Abstract
Background: Bronchial asthma is an inflammatory airway disease with an ever-increasing incidence. Therefore, innovative management strategies are urgently needed. MicroRNAs are small molecules that play a key role in lungs cellular functions and are involved in chronic inflammatory diseases, such as bronchial asthma. This study aims to compare microRNA serum expression between subjects with asthma, obesity, the most common co-morbidity in asthma, and healthy controls to obtain a specific expression profile specifically related to lung inflammation. Methods: We collected serum samples from a prospective cohort of 25 sex-matched subjects to determine circulating miRNAs through a quantitative RT-PCR. Moreover, we performed an in silico prediction of microRNA target genes linked to lung inflammation. Results: Asthmatic patients had a significant lower expression of hsa-miR-34a-5p, 181a-5p and 146a-5p compared to both obese and healthy ones suggesting microRNAs’ specific involvement in the regulation of lungs inflammatory response. Indeed, using in silico analysis, we identified microRNAs novel target genes as GATA family, linked to the inflammatory-related pathway. Conclusions: This study identifies a novel circulating miRNAs expression profile with promising potentials for asthma clinical evaluations and management. Further and larger investigations will be needed to confirm the potential role of microRNA as a clinical marker of bronchial asthma and eventually of pharmacological treatment response.
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Affiliation(s)
- Davida Mirra
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy
| | - Erika Cione
- Department of Pharmacy, Health and Nutritional Sciences-Department of Excellence 2018–2022, University of Calabria, 87036 Rende, CS, Italy
| | - Giuseppe Spaziano
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy
| | - Renata Esposito
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy
| | - Mario Sorgenti
- Respiratory Diseases in Primary Care, ASP Catanzaro, 88100 Catanzaro, Italy
| | - Elisabetta Granato
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, 80138 Naples, Italy
| | - Ida Cerqua
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, 80138 Naples, Italy
| | - Lucia Muraca
- Department of Primary Care, ASP Catanzaro, 88100 Catanzaro, Italy
| | - Pasquale Iovino
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy
| | - Luca Gallelli
- Clinical Pharmacology and Pharmacovigilance Unit, Department of Health Sciences, Mater Domini Hospital, University of Catanzaro, 88100 Catanzaro, Italy
- Correspondence:
| | - Bruno D’Agostino
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy
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Esposito R, Spaziano G, Giannattasio D, Ferrigno F, Liparulo A, Rossi A, Roviezzo F, Sessa M, Falciani M, Berrino L, Polverino M, Polverino F, D'Agostino B. Montelukast Improves Symptoms and Lung Function in Asthmatic Women Compared With Men. Front Pharmacol 2019; 10:1094. [PMID: 31611790 PMCID: PMC6769077 DOI: 10.3389/fphar.2019.01094] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 08/26/2019] [Indexed: 12/28/2022] Open
Abstract
Purpose: Gender differences exist in the prevalence of asthma and allergic diseases, partially due to the effects of sex hormones on the development of allergic manifestations. Women, compared with men, are more prone to suffer allergic asthma, experience difficulties in controlling asthma symptoms, and show adverse responses to drugs. However, there are knowledge gaps on the effectiveness of anti-leukotrienes drugs on lung function, symptoms, and pulmonary and systemic inflammation in adult asthmatic women compared with men. We conducted a prospective cohort study to characterize the effectiveness of an anti-leukotrienes drug, montelukast (MS), in asthmatic adult women and men. Methods: Twenty-one asthmatic subjects (11 women and 10 men), who were on low-dose inhaled corticosteroids (ICS), were treated with MS. The optimal control of the symptoms was achieved in both groups according to the Global Initiative for Asthma guidelines. At enrollment, and after 13 weeks from the beginning of MS, pulmonary function tests and asthma control tests were performed, and the fraction of exhaled nitric oxide and blood eosinophils levels were measured. Results: From baseline until the end of the study, women treated with MS + ICS had better control of the asthmatic symptoms, defined as higher asthma control test (ACT) score (17.00 ± 1.07 to 23.36 ± 0.45; p < 0.0015), improved pulmonary function [with higher forced expiratory volume in 1 s (from 77.25 ± 6.79 to 103.88 ± 6.24; p < 0.0077)], and forced vital capacity (from 91.95 ± 6.81 to 113.17 ± 4.79; p < 0.0183) compared with men. Interestingly, MS + ICS-treated women had significantly lower levels of blood eosinophils (from 5.27 ± 0.30 to 3.30 ± 0.31; p < 0.0449) and exhaled nitric oxide (from 44.70 ± 7.30 to 25.20 ± 3.90; p < 0.0294) compared with men. Conclusion: The treatment with MS, added to ICS, in women leads to better control of symptoms, better management of lung function, and decreased inflammation levels compared with ICS + MS treatment in men.
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Affiliation(s)
- Renata Esposito
- Department of Experimental Medicine, Section of Pharmacology "L. Donatelli", University of Campania "L. Vanvitelli", Naples, Italy
| | - Giuseppe Spaziano
- Department of Experimental Medicine, Section of Pharmacology "L. Donatelli", University of Campania "L. Vanvitelli", Naples, Italy
| | | | | | - Angela Liparulo
- Department of Experimental Medicine, Section of Pharmacology "L. Donatelli", University of Campania "L. Vanvitelli", Naples, Italy
| | - Antonietta Rossi
- Department of Pharmacy, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Fiorentina Roviezzo
- Department of Pharmacy, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Maurizio Sessa
- Department of Experimental Medicine, Section of Pharmacology "L. Donatelli", University of Campania "L. Vanvitelli", Naples, Italy.,Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | | | - Liberato Berrino
- Department of Experimental Medicine, Section of Pharmacology "L. Donatelli", University of Campania "L. Vanvitelli", Naples, Italy
| | - Mario Polverino
- Pulmonary and Critical Care Medicine, Ospedale Scarlato, Scafati, Italy
| | - Francesca Polverino
- Asthma and Airway Disease Research Center, University of Arizona, Tucson, AZ, United States
| | - Bruno D'Agostino
- Department of Experimental Medicine, Section of Pharmacology "L. Donatelli", University of Campania "L. Vanvitelli", Naples, Italy
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D'Agostino B, Sgambato M, Esposito R, Spaziano G. N/OFQ-NOP System and Airways. Handb Exp Pharmacol 2019; 254:313-322. [PMID: 30725285 DOI: 10.1007/164_2018_202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Asthma is a heterogeneous chronic inflammatory disease of the airways. The most prevalent form is atopic asthma, which is initiated by the exposure to (inhaled) allergens. Intermittent attacks of breathlessness, airways hyperresponsiveness, wheezing, coughing, and resultant allergen-specific immune responses characterize the disease. Nociceptin/OFQ-NOP receptor system is able to combine anti-hyperresponsiveness and immunomodulatory actions. In particular, N/OFQ is able to inhibit airways microvascular leakage and bronchoconstriction through a presynaptic and non-opioid mechanism of action that blocks tachykinin release. Moreover, it also acts on allergenic sensitization because it is able to modulate the immune response that triggers the development of airway hyperresponsiveness through an interaction on cell membranes of dendritic cells (DCs) that are generally responsible to start and sustain allergic T helper 2 (TH2)-cell responses to inhaled allergens in asthma. In asthmatic patients, sputum showed elevated N/OFQ levels that are related to increased eosinophil counts. The addition of exogenous N/OFQ in sputum obtained from patients with severe asthma attenuated eosinophils migration and release of inflammatory mediators. These observations confirmed that elevated endogenous N/OFQ levels in asthmatic sputum were lower than the ones required to exert beneficial effects, suggesting that supplementation with exogenous N/OFQ may need. In conclusion, the innovative role of N/OFQ in counteracting airways inflammation/hyperresponsiveness opens new potential targets/strategies in asthma treatment.
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Affiliation(s)
- Bruno D'Agostino
- Department of Experimental Medicine, Section of Pharmacology L. Donatelli, University of Campania "L. Vanvitelli", Naples, Italy.
| | - Manuela Sgambato
- Department of Experimental Medicine, Section of Pharmacology L. Donatelli, University of Campania "L. Vanvitelli", Naples, Italy
| | - Renata Esposito
- Department of Experimental Medicine, Section of Pharmacology L. Donatelli, University of Campania "L. Vanvitelli", Naples, Italy
| | - Giuseppe Spaziano
- Department of Experimental Medicine, Section of Pharmacology L. Donatelli, University of Campania "L. Vanvitelli", Naples, Italy
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Tartaglione G, Spaziano G, Sgambato M, Russo TP, Liparulo A, Esposito R, Mirra S, Filosa R, Roviezzo F, Polverino F, D'Agostino B. Nociceptin/Orphanin Fq in inflammation and remodeling of the small airways in experimental model of airway hyperresponsiveness. Physiol Rep 2018; 6:e13906. [PMID: 30370666 PMCID: PMC6204362 DOI: 10.14814/phy2.13906] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 09/28/2018] [Accepted: 09/28/2018] [Indexed: 12/20/2022] Open
Abstract
It is widely recognized that airway inflammation and remodeling play a key role not only in the central airway but also small airway pathology during asthma. Nociceptin/Orphanin FQ (N/OFQ), an endogenous peptide, and its receptor N/OFQ peptide (NOP) are involved in airway hyperresponsiveness (AHR). We studied a murine model of AHR in order to understand the role of N/OFQ in the inflammation and remodeling of the small airways. Balb/c mice were sensitized to ovalbumin (OVA). At days 0 and 7 (pre-OVA sensitization) or from day 21 to 23 (post-OVA sensitization), the mice were treated intraperitoneally with N/OFQ or saline solution. After the last OVA challenge, all OVA-sensitized mice were aerosol-challenged with 1% OVA in PBS for 48 h, and then euthanized. Small airway compliance (sCaw ) was measured and lung samples were collected for histological and molecular evaluations such as perimeter and diameter of small airway, total wall area, airway smooth muscle (ASM) thickness and number of alveolar attachments. Both pre- and post-OVA sensitization N/OFQ treatments induced: (1) increases in sCaw ; (2) reduction of the bronchial wall thickness; (3) attenuation of the hyperplastic phase of airway smooth muscle mass; and (4) protection against loss of alveolar attachments compared with saline solution treatments. These results suggest that N/OFQ protects against inflammation, and mechanical damage and remodeling of small airways caused by OVA sensitization, suggesting a new potential therapeutic target for asthma.
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Affiliation(s)
- Gioia Tartaglione
- Department of Experimental MedicineSchool of MedicineSection of PharmacologyUniversity of Campania “L. Vanvitelli”NaplesItaly
| | - Giuseppe Spaziano
- Department of Experimental MedicineSchool of MedicineSection of PharmacologyUniversity of Campania “L. Vanvitelli”NaplesItaly
| | - Manuela Sgambato
- Department of Experimental MedicineSchool of MedicineSection of PharmacologyUniversity of Campania “L. Vanvitelli”NaplesItaly
| | - Teresa Palmira Russo
- Department of Experimental MedicineSchool of MedicineSection of PharmacologyUniversity of Campania “L. Vanvitelli”NaplesItaly
| | - Angela Liparulo
- Department of Experimental MedicineSchool of MedicineSection of PharmacologyUniversity of Campania “L. Vanvitelli”NaplesItaly
| | - Renata Esposito
- Department of Experimental MedicineSchool of MedicineSection of PharmacologyUniversity of Campania “L. Vanvitelli”NaplesItaly
| | - Salvatore Mirra
- Department of Experimental MedicineSchool of MedicineSection of PharmacologyUniversity of Campania “L. Vanvitelli”NaplesItaly
| | - Rosanna Filosa
- Department of Experimental MedicineSchool of MedicineSection of PharmacologyUniversity of Campania “L. Vanvitelli”NaplesItaly
| | | | | | - Bruno D'Agostino
- Department of Experimental MedicineSchool of MedicineSection of PharmacologyUniversity of Campania “L. Vanvitelli”NaplesItaly
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Lung Mesenchymal Stem Cells Ameliorate Elastase-Induced Damage in an Animal Model of Emphysema. Stem Cells Int 2018; 2018:9492038. [PMID: 29731780 PMCID: PMC5872595 DOI: 10.1155/2018/9492038] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 11/15/2017] [Accepted: 12/21/2017] [Indexed: 12/28/2022] Open
Abstract
Pulmonary emphysema is a respiratory condition characterized by alveolar destruction that leads to airflow limitation and reduced lung function. Although with extensive research, the pathophysiology of emphysema is poorly understood and effective treatments are still missing. Evidence suggests that mesenchymal stem cells (MSCs) possess the ability to engraft the injured tissues and induce repair via a paracrine effect. Thus, the aim of this study was to test the effects of the intratracheal administration of lung-derived mouse MSCs in a model of elastase-induced emphysema. Pulmonary function (static lung compliance) showed an increased stiffness induced by elastase, while morphometric findings (mean linear intercept and tissue/alveolar area) confirmed the severity of alveolar disruption. Contrarily, MSC administration partially restored lung elasticity and alveolar architecture. In the absence of evidence that MSCs acquired epithelial phenotype, we detected an increased proliferative activity of aquaporin 5- and surfactant protein C-positive lung cells, suggesting MSC-driven paracrine mechanisms. The data indicate the mediation of hepatocyte growth factor in amplifying MSC-driven tissue response after injury. Our study shed light on supportive properties of lung-derived MSCs, although the full identification of mechanisms orchestrated by MSCs and responsible for epithelial repair after injury is a critical aspect yet to be achieved.
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11
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Bruno F, Spaziano G, Liparulo A, Roviezzo F, Nabavi SM, Sureda A, Filosa R, D'Agostino B. Recent advances in the search for novel 5-lipoxygenase inhibitors for the treatment of asthma. Eur J Med Chem 2017; 153:65-72. [PMID: 29133059 DOI: 10.1016/j.ejmech.2017.10.020] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 10/06/2017] [Accepted: 10/09/2017] [Indexed: 02/06/2023]
Abstract
The products of 5-lipoxygenase are synthesized and released in the airway when an asthmatic reaction occurs. 5-lipoxygenase via arachidonic acid metabolism produces leukotrienes that mediate bronchoconstriction and inflammatory modifications essential in the pathophysiology of asthma. Until to now, only one approved 5-LO inhibitor, zileuton, can be found as a potential therapy for asthma. With the increasing number of indications for anti-leukotriene (anti-LT) drugs, the development of 5-LO inhibitor agents becomes increasingly important. The present MiniReview reports an update on 5-LO inhibitors currently under clinical investigation. In addition, the latest advances focused on the development of new 5-lipoxygenase inhibitors as asthma anti-inflammatory agents are also discussed.
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Affiliation(s)
- Ferdinando Bruno
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Via Costantinopoli, 16, 80138 Naples, Italy
| | - Giuseppe Spaziano
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Via Costantinopoli, 16, 80138 Naples, Italy
| | - Angela Liparulo
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Via Costantinopoli, 16, 80138 Naples, Italy
| | | | - Seyed Mohammed Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Antoni Sureda
- Research Group on Community Nutrition and Oxidative Stress (NUCOX), CIBEROBN (Physiopathology of Obesity and Nutrition CB12/03/30038), University of Balearic Islands, Palma de Mallorca E-07122, Balearic Islands, Spain
| | - Rosanna Filosa
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Via Costantinopoli, 16, 80138 Naples, Italy.
| | - Bruno D'Agostino
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Via Costantinopoli, 16, 80138 Naples, Italy
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12
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Sportiello L, Rafaniello C, Sullo MG, Nica M, Scavone C, Bernardi FF, Colombo DM, Rossi F. No substantial gender differences in suspected adverse reactions to ACE inhibitors and ARBs: results from spontaneous reporting system in Campania Region. Expert Opin Drug Saf 2017; 15:101-107. [PMID: 27875922 DOI: 10.1080/14740338.2016.1225720] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Today, there is a poor knowledge about gender differences in adverse drug reactions (ADRs) to cardiovascular drugs such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). Therefore, the aim of this study was to analyze spontaneous reports of suspected ADRs induced by ACE-inhibitors and ARBs, between January 2001 and June 2015, recorded in a Region of Southern Italy (Campania Region). METHODS We performed a descriptive gender-related analysis of regional safety data, obtained from the spontaneous reporting system. RESULTS In the considered period, 772 suspected ADRs to ACE inhibitors and ARBs (in monotherapy or in combination) were reported with a slightly higher frequency in men compared with women. In both genders, the most involved category was ARBs in combination, whereas the most prescribed active substance was ramipril. General and administration site conditions, vascular disorders and modification of laboratory parameters were more common in men, while respiratory disorders were most common in women. In 88.2% of cases, not serious ADRs were described more by men than women. CONCLUSIONS This analysis suggested no substantial gender differences. Further studies such as randomized population studies or meta-analysis of ACE inhibitors and ARBs randomized studies are needed to clarify whether gender differences exist in the safety profile of these drugs.
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Affiliation(s)
- Liberata Sportiello
- a Regional Centre of Pharmacovigilance and Pharmacoepidemiology, Department of Experimental Medicine , Second University of Naples , Naples , Italy
| | - Concetta Rafaniello
- a Regional Centre of Pharmacovigilance and Pharmacoepidemiology, Department of Experimental Medicine , Second University of Naples , Naples , Italy
| | - Maria Giuseppa Sullo
- a Regional Centre of Pharmacovigilance and Pharmacoepidemiology, Department of Experimental Medicine , Second University of Naples , Naples , Italy
| | - Mihaela Nica
- b Novartis Farma Italia , Value & Access Department , Varese , Italy
| | - Cristina Scavone
- a Regional Centre of Pharmacovigilance and Pharmacoepidemiology, Department of Experimental Medicine , Second University of Naples , Naples , Italy
| | - Francesca Futura Bernardi
- a Regional Centre of Pharmacovigilance and Pharmacoepidemiology, Department of Experimental Medicine , Second University of Naples , Naples , Italy
| | | | - Francesco Rossi
- a Regional Centre of Pharmacovigilance and Pharmacoepidemiology, Department of Experimental Medicine , Second University of Naples , Naples , Italy
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13
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Spaziano G, Sorrentino R, Matteis M, Malgieri G, Sgambato M, Russo TP, Terlizzi M, Roviezzo F, Rossi F, Pinto A, Fattorusso R, D'Agostino B. Nociceptin reduces the inflammatory immune microenvironment in a conventional murine model of airway hyperresponsiveness. Clin Exp Allergy 2017; 47:208-216. [PMID: 27562660 DOI: 10.1111/cea.12808] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 07/25/2016] [Accepted: 08/19/2016] [Indexed: 12/17/2022]
Abstract
BACKGROUND Nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) are involved in airway hyperresponsiveness (AHR) and inflammation. However, the role of nociceptin at modulating the inflammatory immune microenvironment in asthma is still unclear. OBJECTIVE To understand the role of N/OFQ in the regulation of a Th2-like environment, we used a conventional murine model of AHR. METHODS Balb/c and CD1 mice were sensitized to ovalbumin (OVA) and treated with saline solution or N/OFQ, at days 0 and 7. A group of Balb/c mice were killed at 7 and 14 days from the first sensitization for the inflammatory profile evaluation while a group of Balb/c and CD1 mice were aerosol-challenged from day 21 to 23 with OVA and killed 24 h later for functional evaluations. RESULTS In OVA-sensitized mice, N/OFQ significantly reduced IL-4+ CD4+ T cells in lymph nodes (LN) and IL-13 in the lungs, while it induced IFN-γ increase in the lung. The efflux of dendritic cells (DCs) to the mediastinic LN and into the lung of OVA-sensitized mice was reduced in N/OFQ-treated and sensitized mice. N/OFQ reduced the expression of CD80 on DCs, indicating its ability to modulate the activation of DCs. In a less prone Th2-like environment mice strain, such as CD1 mice, N/OFQ did not modify lung resistances as observed in BALB/c mice. Finally, spectroscopic data showed the N/OFQ was able to interact onto the membrane of DCs obtained from Balb/c rather than CD1 mice, indicating its ability to modulate AHR in a Th2-like environment with a direct activity on DCs. CONCLUSIONS AND CLINICAL RELEVANCE Our data confirmed the capability of N/OFQ to modulate the immune microenvironment in the lung of Th2-biased, OVA-sensitized Balb/c mice, suggesting N/OFQ-NOP axis as a novel pharmacological tool to modulate the inflammatory immune microenvironment in asthma.
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Affiliation(s)
- G Spaziano
- Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy
| | - R Sorrentino
- Department of Pharmacy (DIFARMA), University of Salerno, Fisciano, Italy
| | - M Matteis
- Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy
| | - G Malgieri
- Department of Environmental, Biological and Pharmaceutical Science and Technology, Second University of Naples, Caserta, Italy
| | - M Sgambato
- Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy
| | - T P Russo
- Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy
| | - M Terlizzi
- Department of Pharmacy (DIFARMA), University of Salerno, Fisciano, Italy
| | - F Roviezzo
- Department of Experimental Pharmacology, University Federico II of Naples, Naples, Italy
| | - F Rossi
- Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy
| | - A Pinto
- Department of Pharmacy (DIFARMA), University of Salerno, Fisciano, Italy
| | - R Fattorusso
- Department of Environmental, Biological and Pharmaceutical Science and Technology, Second University of Naples, Caserta, Italy
| | - B D'Agostino
- Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy
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14
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Gallelli L, Falcone D, Cannataro R, Perri M, Serra R, Pelaia G, Maselli R, Savino R, Spaziano G, D’Agostino B. Theophylline action on primary human bronchial epithelial cells under proinflammatory stimuli and steroidal drugs: a therapeutic rationale approach. Drug Des Devel Ther 2017; 11:265-272. [PMID: 28176948 PMCID: PMC5271379 DOI: 10.2147/dddt.s118485] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Theophylline is a natural compound present in tea. Because of its property to relax smooth muscle it is used in pharmacology for the treatment of airway diseases (ie, chronic obstructive pulmonary disease, asthma). However, this effect on smooth muscle is dose dependent and it is related to the development of side effects. Recently, an increasing body of evidence suggests that theophylline, at low concentrations, also has anti-inflammatory effects related to the activation of histone deacetylases. In this study, we evaluated the effects of theophylline alone and in combination with corticosteroids on human bronchial epithelial cells under inflammatory stimuli. Theophylline administrated alone was not able to reduce growth-stimulating signaling via extracellular signal-regulated kinases activation and matrix metalloproteases release, whereas it strongly counteracts this biochemical behavior when administered in the presence of corticosteroids. These data provide scientific evidence for supporting the rationale for the pharmacological use of theophylline and corticosteroid combined drug.
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Affiliation(s)
- Luca Gallelli
- Department of Health Science, University of Catanzaro, Catanzaro
| | - Daniela Falcone
- Department of Health Science, University of Catanzaro, Catanzaro
| | - Roberto Cannataro
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende
| | - Mariarita Perri
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende
| | - Raffaele Serra
- Department of Medical and Surgical Sciences, University of Catanzaro, Catanzaro
| | - Girolamo Pelaia
- Department of Medical and Surgical Sciences, University of Catanzaro, Catanzaro
| | - Rosario Maselli
- Department of Medical and Surgical Sciences, University of Catanzaro, Catanzaro
| | - Rocco Savino
- Department of Health Science, University of Catanzaro, Catanzaro
| | - Giuseppe Spaziano
- Department of Experimental Medicine, School of Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy
| | - Bruno D’Agostino
- Department of Experimental Medicine, School of Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy
- Correspondence: Bruno D’Agostino, Department of Experimental Medicine, School of Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 115, 80138 Naples, Italy, Tel +39 81 566 5882, Email
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15
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New Role of Adult Lung c-kit + Cells in a Mouse Model of Airway Hyperresponsiveness. Mediators Inflamm 2016; 2016:3917471. [PMID: 28090152 PMCID: PMC5206449 DOI: 10.1155/2016/3917471] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Revised: 10/05/2016] [Accepted: 11/10/2016] [Indexed: 12/16/2022] Open
Abstract
Structural changes contribute to airway hyperresponsiveness and airflow obstruction in asthma. Emerging evidence points to the involvement of c-kit+ cells in lung homeostasis, although their potential role in asthma is unknown. Our aim was to isolate c-kit+ cells from normal mouse lungs and to test whether these cells can interfere with hallmarks of asthma in an animal model. Adult mouse GFP-tagged c-kit+ cells, intratracheally delivered in the ovalbumin-induced airway hyperresponsiveness, positively affected airway remodeling and improved airway function. In bronchoalveolar lavage fluid of cell-treated animals, a reduction in the number of inflammatory cells and in IL-4, IL-5, and IL-13 release, along with an increase of IL-10, was observed. In MSC-treated mice, the macrophage polarization to M2-like subset may explain, at least in part, the increment in the level of anti-inflammatory cytokine IL-10. After in vitro stimulation of c-kit+ cells with proinflammatory cytokines, the indoleamine 2,3-dioxygenase and TGFβ were upregulated. These data, together with the increased apoptosis of inflammatory cells in vivo, indicate that c-kit+ cells downregulate immune response in asthma by influencing local environment, possibly by cell-to-cell contact combined to paracrine action. In conclusion, intratracheally administered c-kit+ cells reduce inflammation, positively modulate airway remodeling, and improve function. These data document previously unrecognized properties of c-kit+ cells, able to impede pathophysiological features of experimental airway hyperresponsiveness.
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16
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Roviezzo F, Sorrentino R, Iacono VM, Brancaleone V, Terlizzi M, Riemma MA, Bertolino A, Rossi A, Matteis M, Spaziano G, Pinto A, D'Agostino B, Cirino G. Disodium cromoglycate inhibits asthma-like features induced by sphingosine-1-phosphate. Pharmacol Res 2016; 113:626-635. [PMID: 27713021 DOI: 10.1016/j.phrs.2016.09.014] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Revised: 07/28/2016] [Accepted: 09/14/2016] [Indexed: 11/17/2022]
Abstract
Compelling evidence suggests the involvement of sphingosine-1-phosphate (S1P) in the pathogenesis of asthma. The systemic administration of S1P causes asthma like features in the mouse involving mast cells. In this study we investigated whether disodium cromoglycate (DSCG), administered as a preventative treatment as in human therapy, could affect S1P effects on airways. BALB/c mice, treated with DSCG, received subcutaneous administration of S1P. Bronchi and pulmonary tissues were collected and functional, molecular and cellular studies were performed. DSCG inhibited S1P-induced airway hyper-reactivity as well as pulmonary inflammation. DSCG decreased the recruitment of solely mast cells and B cells in the lung. IgE serum levels, prostaglandin D2, mucus production and IL-13 were also reduced when mice were pretreated with DSCG. S1P induced pulmonary expression of CD23 on T and B cells, that was reversed by DSCG. Conversely, S1P failed to upregulate CD23 in mast cell-deficient Kit W-sh/W-sh mice. In conclusion we have shown that DSCG inhibits S1P-induced asthma like features in the mouse. This beneficial effect is due to a regulatory action on mast cell activity, and in turn to an inhibition of IgE-dependent T and B cells responses.
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Affiliation(s)
| | | | | | | | - Michela Terlizzi
- Department of Pharmacy (DIFARMA), University of Salerno, Salerno, Italy
| | | | - Antonio Bertolino
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Antonietta Rossi
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Maria Matteis
- Department of Experimental Medicine L. Donatelli, Second University of Naples, Naples, Italy
| | - Giuseppe Spaziano
- Department of Experimental Medicine L. Donatelli, Second University of Naples, Naples, Italy
| | - Aldo Pinto
- Department of Pharmacy (DIFARMA), University of Salerno, Salerno, Italy
| | - Bruno D'Agostino
- Department of Experimental Medicine L. Donatelli, Second University of Naples, Naples, Italy.
| | - Giuseppe Cirino
- Department of Pharmacy, University of Naples Federico II, Naples, Italy.
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17
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Toll L, Bruchas MR, Calo' G, Cox BM, Zaveri NT. Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems. Pharmacol Rev 2016; 68:419-57. [PMID: 26956246 PMCID: PMC4813427 DOI: 10.1124/pr.114.009209] [Citation(s) in RCA: 224] [Impact Index Per Article: 24.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The NOP receptor (nociceptin/orphanin FQ opioid peptide receptor) is the most recently discovered member of the opioid receptor family and, together with its endogenous ligand, N/OFQ, make up the fourth members of the opioid receptor and opioid peptide family. Because of its more recent discovery, an understanding of the cellular and behavioral actions induced by NOP receptor activation are less well developed than for the other members of the opioid receptor family. All of these factors are important because NOP receptor activation has a clear modulatory role on mu opioid receptor-mediated actions and thereby affects opioid analgesia, tolerance development, and reward. In addition to opioid modulatory actions, NOP receptor activation has important effects on motor function and other physiologic processes. This review discusses how NOP pharmacology intersects, contrasts, and interacts with the mu opioid receptor in terms of tertiary structure and mechanism of receptor activation; location of receptors in the central nervous system; mechanisms of desensitization and downregulation; cellular actions; intracellular signal transduction pathways; and behavioral actions with respect to analgesia, tolerance, dependence, and reward. This is followed by a discussion of the agonists and antagonists that have most contributed to our current knowledge. Because NOP receptors are highly expressed in brain and spinal cord and NOP receptor activation sometimes synergizes with mu receptor-mediated actions and sometimes opposes them, an understanding of NOP receptor pharmacology in the context of these interactions with the opioid receptors will be crucial to the development of novel therapeutics that engage the NOP receptor.
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Affiliation(s)
- Lawrence Toll
- Torrey Pines Institute for Molecular Studies, Port St. Lucie, Florida (L.T.); Departments of Anesthesiology, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri (M.R.B.); Section of Pharmacology, Department of Medical Science, and National Institute of Neurosciences, University of Ferrara, Ferrara, Italy (G.C.); Professor of Pharmacology & Neuroscience, Uniformed Services University, Bethesda, Maryland (B.M.C.); and Astraea Therapeutics, LLC, Mountain View, California (N.T.Z.)
| | - Michael R Bruchas
- Torrey Pines Institute for Molecular Studies, Port St. Lucie, Florida (L.T.); Departments of Anesthesiology, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri (M.R.B.); Section of Pharmacology, Department of Medical Science, and National Institute of Neurosciences, University of Ferrara, Ferrara, Italy (G.C.); Professor of Pharmacology & Neuroscience, Uniformed Services University, Bethesda, Maryland (B.M.C.); and Astraea Therapeutics, LLC, Mountain View, California (N.T.Z.)
| | - Girolamo Calo'
- Torrey Pines Institute for Molecular Studies, Port St. Lucie, Florida (L.T.); Departments of Anesthesiology, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri (M.R.B.); Section of Pharmacology, Department of Medical Science, and National Institute of Neurosciences, University of Ferrara, Ferrara, Italy (G.C.); Professor of Pharmacology & Neuroscience, Uniformed Services University, Bethesda, Maryland (B.M.C.); and Astraea Therapeutics, LLC, Mountain View, California (N.T.Z.)
| | - Brian M Cox
- Torrey Pines Institute for Molecular Studies, Port St. Lucie, Florida (L.T.); Departments of Anesthesiology, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri (M.R.B.); Section of Pharmacology, Department of Medical Science, and National Institute of Neurosciences, University of Ferrara, Ferrara, Italy (G.C.); Professor of Pharmacology & Neuroscience, Uniformed Services University, Bethesda, Maryland (B.M.C.); and Astraea Therapeutics, LLC, Mountain View, California (N.T.Z.)
| | - Nurulain T Zaveri
- Torrey Pines Institute for Molecular Studies, Port St. Lucie, Florida (L.T.); Departments of Anesthesiology, and Neuroscience, Washington University School of Medicine, St. Louis, Missouri (M.R.B.); Section of Pharmacology, Department of Medical Science, and National Institute of Neurosciences, University of Ferrara, Ferrara, Italy (G.C.); Professor of Pharmacology & Neuroscience, Uniformed Services University, Bethesda, Maryland (B.M.C.); and Astraea Therapeutics, LLC, Mountain View, California (N.T.Z.)
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18
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Gavioli EC, Calo' G. Nociceptin/orphanin FQ receptor antagonists as innovative antidepressant drugs. Pharmacol Ther 2013; 140:10-25. [PMID: 23711793 DOI: 10.1016/j.pharmthera.2013.05.008] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Accepted: 05/07/2013] [Indexed: 12/21/2022]
Abstract
Nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) were identified in the mid 90s as a novel peptidergic system structurally related to opioids. A growing body of preclinical evidence suggests that blockade of NOP receptors evokes antidepressant-like actions. These have been explored using a range of compounds (peptide and non peptide antagonists), across different species (rat and mouse) and assays (behavioral despair and chronic mild stress) suggesting a robust and consistent antidepressant-like effect. Moreover, rats and mice knockout for the NOP receptor gene display an antidepressant-like phenotype in behavioral despair assays. Electrophysiological, immunohistochemical and neurochemical studies point to an important role played by monoaminergic systems, particularly 5-HTergic, in mediating the antidepressant-like properties of NOP antagonists. However other putative mechanisms of action, including modulation of the CRF system, circadian rhythm and a possible neuroendocrine-immune control might be involved. A close relationship between the N/OFQ-NOP receptor system and stress responses is well described in the literature. Stressful situations also alter endocrine, behavioral and neurochemical parameters in rats and chronic administration of a NOP antagonist restored these alterations. Interestingly, clinical findings showed that plasma N/OFQ levels were significantly altered in major and post-partum depression, and bipolar disease patients. Collectively, data in the literature support the notion that blockade of NOP receptor signaling could be a novel and interesting strategy for the development of innovative antidepressants.
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Affiliation(s)
- Elaine Cristina Gavioli
- Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte, 59078-970 Natal-RN, Brazil.
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19
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Update on anticytokine treatment for asthma. BIOMED RESEARCH INTERNATIONAL 2013; 2013:104315. [PMID: 23853765 PMCID: PMC3703384 DOI: 10.1155/2013/104315] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Accepted: 06/07/2013] [Indexed: 12/18/2022]
Abstract
Current advances in the knowledge of asthma pathobiology suggest that anticytokine therapies can be potentially useful for the treatment of this complex and heterogeneous airway disease. Recent evidence is accumulating in support of the efficacy of anti-IL-4, anti-IL-5, and anti-IL-13 drugs. Therefore, these new developments are now changing the global scenario of antiasthma therapies, especially with regard to more severe disease. Current findings referring to variability of individual therapeutic responses highlight that the different asthma subtypes need to be well characterized, in order to implement phenotype-targeted treatments which in the near future will hopefully be mainly based on cytokine-directed biologics.
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20
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Sullo N, Roviezzo F, Matteis M, Ianaro A, Calò G, Guerrini R, De Gruttola L, Spaziano G, Cirino G, Rossi F, D'Agostino B. Nociceptin/orphanin FQ receptor activation decreases the airway hyperresponsiveness induced by allergen in sensitized mice. Am J Physiol Lung Cell Mol Physiol 2013; 304:L657-64. [PMID: 23502511 DOI: 10.1152/ajplung.00358.2012] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Several studies suggest that the N/OFQ (nociceptin/orphanin FQ)-NOP (N/OFQ peptide) receptor pathway is involved in airway physiology. We previously demonstrated a modulation of the endogenous N/OFQ levels in allergen-sensitized mice. Here, we investigated the effects of NOP receptor activation in allergen sensitization using a murine model of allergen-induced airway hyperresponsiveness (AHR). BALB/c mice were intraperitoneally treated with the NOP receptor agonist UFP-112, either during the sensitization phase (30 min before ovalbumin administration) or at the end of sensitization process (15 min before bronchopulmonary reactivity evaluation). At day 21 from the first allergen exposure, bronchopulmonary reactivity and total and differential cell count in bronchoalveolar lavage fluid were evaluated. In a separate set of experiments cell proliferation in lymphocytes, cytokine levels, IgE serum levels, and the effect of UFP-112 on IL-13-induced AHR were evaluated. Pretreatment with UFP-112, during the sensitization phase, caused a significant reduction in allergen-induced AHR and total cell lung infiltration. No effect on allergen-induced AHR was observed when the treatment was performed at the end of sensitization process, on tissues harvested from OVA-sensitized mice and on IL-13-induced AHR. The in vitro proliferative response of lymphocytes was significantly reduced by pretreatment during the sensitization phase with UFP-112. This effect was paralleled by a significant modulation of cytokine secretion in pulmonary tissues and lymphocytes. In conclusion, we demonstrated a role for the NOP receptor and N/OFQ pathway in the AHR induced by allergen, probably through a modulation of the immune response that triggers the development of AHR that involves pro- and anti-inflammatory cytokines.
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Affiliation(s)
- Nikol Sullo
- Department of Experimental Medicine-Section of Pharmacology, Faculty of Medicine and Surgery, 2nd University of Naples, 80136 Naples, Italy
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21
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Singh SR, Sullo N, D'Agostino B, Brightling CE, Lambert DG. The effects of nociceptin peptide (N/OFQ)-receptor (NOP) system activation in the airways. Peptides 2013; 39:36-46. [PMID: 23123316 DOI: 10.1016/j.peptides.2012.10.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Revised: 10/17/2012] [Accepted: 10/22/2012] [Indexed: 11/20/2022]
Abstract
The heptadecapeptide nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand for the N/OFQ peptide (NOP) receptor. It is cleaved from a larger precursor identified as prepronociceptin (ppN/OFQ). NOP is a member of the seven transmembrane-spanning G-protein coupled receptor (GPCR) family. ppN/OFQ and NOP receptors are widely distributed in different human tissues. Asthma is a complex heterogeneous disease characterized by variable airflow obstruction, bronchial hyper-responsiveness and chronic airway inflammation. Limited therapeutic effectiveness of currently available asthma therapies warrants identification of new drug compounds. Evidence from animal studies suggests that N/OFQ modulates airway contraction and inflammation. Interestingly up regulation of the N/OFQ-NOP system reduces airway hyper-responsiveness. In contrast, inflammatory cells central to the inflammatory response in asthma may be both sources of N/OFQ and respond to NOP activation. Hence paradoxical dysregulation of the N/OFQ-NOP system may potentially play an important role in regulating airway inflammation and airway tone. To date there is no data on N/OFQ-NOP expression in the human airways. Therefore, the potential role of N/OFQ-NOP system in asthma is unknown. This review focuses on its physiological effects within airways and potential value as a novel asthma therapy.
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Affiliation(s)
- Shailendra R Singh
- Department of Cardiovascular Sciences (Pharmacology and Therapeutics Group), Division of Anaesthesia, Critical Care and Pain Management, University of Leicester, Leicester Royal Infirmary, Leicester, UK.
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Sauriyal DS, Jaggi AS, Singh N. Extending pharmacological spectrum of opioids beyond analgesia: multifunctional aspects in different pathophysiological states. Neuropeptides 2011; 45:175-88. [PMID: 21208657 DOI: 10.1016/j.npep.2010.12.004] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2010] [Revised: 12/06/2010] [Accepted: 12/07/2010] [Indexed: 11/29/2022]
Abstract
Opioids are well known to exert potent central analgesic actions. In recent years, the numerous studies have unfolded the critical role of opioids in the pathophysiology of various diseases as well as in biological phenomenon of therapeutic interest. The endogenous ligands of opioid receptors are derived from three independent genes and their appropriate processing yields the major representative opioid peptides beta-endorphin, met-enkephalin, leu-enkephalin and dynorphin, respectively. These peptides and their derivatives exhibit different affinity and selectivity for the mu-, delta- and kappa-receptors located on the central and the peripheral neurons, neuroendocrine, immune, and mucosal cells and on many other organ systems. The present review article highlights the role of these peptides in central nervous system disorders such as depression, anxiety, epilepsy, and stress; gastrointestinal disorders such as diarrhea, postoperative ileus, ulceration, and irritable bowel syndrome; immune system and related inflammatory disorders such as osteoarthritis and rheumatoid arthritis; and others including respiratory, alcoholism and obesity/binge eating. Furthermore, the key role of opioids in different forms of pre- and post-conditioning including ischemic and pharmacological along with in remote preconditioning has also been described.
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Largent-Milnes TM, Vanderah TW. Recently patented and promising ORL-1 ligands: where have we been and where are we going? Expert Opin Ther Pat 2010; 20:291-305. [PMID: 20180617 DOI: 10.1517/13543771003602004] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
IMPORTANCE OF THE FIELD The interactions of nociceptin/orphanin FQ (N/OFQ) and the opioid receptor-like receptor 1 (nociceptin opioid peptide--NOP) have been implicated in a variety of systems including cardiovascular, respiratory, immune, and the central and peripheral nervous systems. AREAS COVERED IN THIS REVIEW To elucidate the endogenous role of the N/OFQ-NOP system through the use of knockout and knockdown animal preparations, though most advances have been made using a host of synthetic agonists and antagonists. This review gives a brief history of the receptor-ligand discovery, the development of these agonists and antagonists within the last 10 years as published, and the therapeutic indications thereof focusing on pain. WHAT THE READER WILL GAIN The use of NOP ligands in pain has been controversial at best; however, there are indications that both agonists and antagonists have a place in the clinical setting for acute and chronic pain. NOP ligands have potential as novel therapeutics, interestingly, when incorporated into a rationally-designed multi-target agent. TAKE HOME MESSAGE The discovery of N/OFQ and NOP opened a new option for the treatment of pain with the potential for a decreased side effect profile. Numerous compounds have been designed to target this system, the most promising of which have mixed profiles.
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Affiliation(s)
- Tally M Largent-Milnes
- University of Arizona, Department of Pharmacology, 1501 N. Campbell Avenue, Tucson, Arizona 85724-5050, USA
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Abstract
Several airway afferent nerve subtypes have been implicated in coughing. These include bronchopulmonary C-fibers, rapidly adapting airway mechanoreceptors and touch-sensitive tracheal Adelta-fibers (also called cough receptors). Although the last two afferent nerve subtypes are primarily sensitive to mechanical stimuli, all can be acted upon by one or more different chemical stimuli. In this review we catalogue the chemical agents that stimulate and/or modulate the activity of the airway afferent nerves involved in cough, and describe the specific mechanisms involved in these effects. In addition, we describe the mechanisms of action of a number of chemical inhibitors of these afferent nerve subtypes, and attempt to relate this information to the regulation of coughing in health and disease.
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Affiliation(s)
- S B Mazzone
- School of Biomedical Sciences, The University of Queensland, St. Lucia QLD 4072, Australia.
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Cui YY, D'Agostino B, Risse PA, Marrocco G, Naline E, Zhang Y, Chen HZ, Finance O, Rinaldi-Carmona M, Rossi F, Advenier C. Cannabinoid CB2 receptor activation prevents bronchoconstriction and airway oedema in a model of gastro-oesophageal reflux. Eur J Pharmacol 2007; 573:206-13. [PMID: 17643417 DOI: 10.1016/j.ejphar.2007.06.040] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2006] [Revised: 06/01/2007] [Accepted: 06/12/2007] [Indexed: 12/30/2022]
Abstract
Cannabinoids have been shown to inhibit sensory nerve activation in guinea-pigs and humans. Their effects are mediated by specific activation of two types of receptors, named CB(1) and CB(2). The purpose of this study was to investigate the effects of WIN 55,212-2, (R)-(+)-[2,3-dihydro-5methyl-3-[(4-morpholino)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthyl)methanone, a non selective agonist of cannabinoid receptors, and JWH 133, (6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran a selective cannabinoid CB(2) receptor agonist, on the sensory nerve component of intraoesophageal (i.oe.) HCl-induced airway microvascular leakage and bronchoconstriction in guinea-pigs. We also tested the effect of WIN 55,212-2 on substance P-induced plasma extravasation and bronchoconstriction. Airway microvascular leakage and bronchoconstriction induced by i.oe. HCl was inhibited by the cannabinoid CB(1)/CB(2) agonist WIN 55,212-2 (0.3-3 mg/kg i.p.) in a dose-dependent manner (maximal inhibition at the dose of 3 mg kg(-1), P<0.01). The effect of WIN 55,212-2 was inhibited by a cannabinoid CB(2) receptor antagonist SR 144528, [N-[(1S)-endo-1,3,3-trimethylbicyclo[2,2,1] heptan-2yl]-5-(-4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide], but not by a CB(1) receptor antagonist, SR 141716, [N-(piperidin-1yl)-5-(-4-chlorophenyl)-1-(2,4dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride]. The cannabinoid CB(2) agonist JWH 133 (0.3-3 mg/kg i.p.) mimicked the inhibitory effect of WIN 55,212-2 on HCl-induced microvascular leakage. Under similar conditions, WIN 55,212-2 (1 mg kg (-1) i.p.) was unable to counteract the airway microvascular leakage and bronchoconstriction induced by substance P. These results suggest that inhibition by WIN 55,212-2 of airway plasma extravasation and bronchoconstriction induced by i.oe. HCl instillation in guinea-pigs is mediated through cannabinoid CB(2) receptor activation.
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MESH Headings
- Airway Obstruction/physiopathology
- Airway Obstruction/prevention & control
- Animals
- Benzoxazines/pharmacology
- Bronchi/blood supply
- Bronchi/drug effects
- Bronchi/physiopathology
- Bronchoconstriction/drug effects
- Bronchoconstriction/physiology
- Camphanes/pharmacology
- Cannabinoids/pharmacology
- Capillary Permeability/drug effects
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Esophagus/drug effects
- Extravasation of Diagnostic and Therapeutic Materials
- Gastroesophageal Reflux/physiopathology
- Gastroesophageal Reflux/prevention & control
- Guinea Pigs
- Hydrochloric Acid/administration & dosage
- Hydrochloric Acid/toxicity
- Male
- Morpholines/pharmacology
- Naphthalenes/pharmacology
- Piperidines/pharmacology
- Pulmonary Edema/physiopathology
- Pulmonary Edema/prevention & control
- Pyrazoles/pharmacology
- Receptor, Cannabinoid, CB1/agonists
- Receptor, Cannabinoid, CB2/agonists
- Receptor, Cannabinoid, CB2/antagonists & inhibitors
- Receptor, Cannabinoid, CB2/physiology
- Respiratory Function Tests/methods
- Rimonabant
- Trachea/blood supply
- Trachea/drug effects
- Trachea/physiopathology
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Affiliation(s)
- Yong-Yao Cui
- Université Versailles St-Quentin, UPRES EA220, Pharmacology, Foch Hospital, 11, rue Guillaume Lenoir, 92150 Suresnes, France
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Brookes ZLS, Stedman EN, Guerrini R, Lawton BK, Calo G, Lambert DG. Proinflammatory and vasodilator effects of nociceptin/orphanin FQ in the rat mesenteric microcirculation are mediated by histamine. Am J Physiol Heart Circ Physiol 2007; 293:H2977-85. [PMID: 17766480 DOI: 10.1152/ajpheart.00448.2007] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand for the N/OFQ peptide receptor (NOP). N/OFQ causes hypotension and vasodilation, and we aimed to determine the role of histamine in inflammatory microvascular responses to N/OFQ. Male Wistar rats (220-300 g, n = 72) were anesthetized with thiopental (30 mg/kg bolus, 40-90 mg x kg(-1) x h(-1) iv), and the mesentery was prepared for fluorescent intravital microscopy using fluorescein isothiocyanate-conjugated BSA (FITC-BSA, 0.25 ml/100 g iv) or 1 microm fluorescently labeled microspheres. N/OFQ (0.6-60 nmol/kg iv) caused hypotension (SAP, baseline: 154 +/- 11 mmHg, 15 nmol/kg N/OFQ: 112 +/- 10 mmHg, P = 0.009), vasodilation (venules: 23.9 +/- 1.2 microm, 26.7 +/- 1.2 microm, P = 0.006), macromolecular leak (interstitial gray level FITC-BSA: 103.7 +/- 3.4, 123.5 +/- 11.8, P = 0.009), and leukocyte adhesion (2.0 +/- 0.9, 15.2 +/- 0.9/100 microm, P = 0.036). Microsphere velocity also decreased (venules: 1,230 +/- 370 microm/s, P = 0.037), but there were no significant changes in blood flow. Flow cytometry measured a concurrent increase in neutrophil expression of cd11b with N/OFQ vs. controls (Geo mean fluorescence: 4.19 +/- 0.13 vs. 2.06 +/- 0.38, P < 0.05). The NOP antagonist [Nphe(1),Arg(14),Lys(15)]N/OFQ-NH(2) (UFP-101; 60 and 150 nmol/kg iv), H(1) and H(2)antagonists pyrilamine (mepyramine, 1 mg/kg iv) and ranitidine (1 mg/kg iv), and mast cell stabilizer cromolyn (1 mg x kg(-1) x min(-1)) also abolished vasodilation and macromolecular leak to N/OFQ in vivo (P < 0.05), but did not affect hypotension. Isolated mesenteric arteries (approximately 200 microm, n = 25) preconstricted with U-46619 were also mounted on a pressure myograph (60 mmHg), and both intraluminally and extraluminally administered N/OFQ (10(-5) M) caused dilation, inhibited by pyrilamine in the extraluminal but not the intraluminal (control: -6.9 +/- 3.8%; N/OFQ: 32.6 +/- 8.4%; pyrilamine: 31.5 +/- 6.8%, n = 18, P < 0.05) experiments. We conclude that, in vivo, mesenteric microvascular dilation and macromolecular leak occur via N/OFQ-NOP-mediated release of histamine from mast cells. Therefore, N/OFQ-NOP has an important role in microvascular inflammation, and this may be targeted during disease, particularly as we have proven that UFP-101 is an effective antagonist of microvascular responses in vivo.
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Affiliation(s)
- Zoë L S Brookes
- University of Sheffield, Academic Anaesthesia Unit and Microcirculation Research Group, Royal Hallamshire Hospital, Sheffield S10 2JF, UK.
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Li HY, Yan X, Xue QL, Zhou YN, Gao Y, Wang R, Liu YM, Ran JT. Effects of nociceptin/orphanin FQ on rats with cathartic colon. World J Gastroenterol 2007; 13:141-5. [PMID: 17206761 PMCID: PMC4065871 DOI: 10.3748/wjg.v13.i1.141] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2006] [Revised: 05/15/2006] [Accepted: 07/10/2006] [Indexed: 02/06/2023] Open
Abstract
AIM To demonstrate the change and effect of nociceptin/orphanin FQ in the colon of rats with cathartic colon. METHODS The cathartic colon model was established by feeding rats rhubarb for 3 mo, the changes of colonic electromyography were investigated by both suspension muscle strips test and serosal recordings of colonic myoelectrical activity. Immunohistochemical staining (S-P methods) and image analysis were used to determine the changes of nociceptin/orphanin FQ in the proximal colon and distal colon of rats with cathartic colon. RESULTS Suspension muscle strips test in vitro showed OFQ (10(-9)-10(-6) mol/L) concentration dependently caused an immediate tonic contraction in the isolated colon. But the increase of tension in cathartic colon was less than control groups (P < 0.01). Intravenous administration of OFQ (1 microg/kg) caused phasic contractions in the proximal colon, while the amplitude of phasic contractions caused by OFQ in cathartic colon was much lower than that in the control groups (2.58 +/- 0.41 vs 4.16 +/- 0.53, t = -2.6, P = 0.012). OFQ was highly expressed in the myenteric plexus of the rat colon but not in the muscle cells. The immunoreactivity of OFQ in the proximal colon in cathartic colon rats decreased significantly compared with the control group (P = 0.001). CONCLUSION Colonic smooth muscle of cathartic colon showed low sensitivity to the stimulation of OFQ, suggesting that it might be caused by the abnormal distribution of OFQ or the abnormalities of receptors, leading to the disorganization of dynamic and incoordinated contractions.
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Affiliation(s)
- Hai-Yan Li
- Department of Geriatrics, 1st Affiliated Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China.
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Abstract
This paper is the 28th consecutive installment of the annual review of research concerning the endogenous opioid system, now spanning over a quarter-century of research. It summarizes papers published during 2005 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity, neurophysiology and transmitter release (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); immunological responses (Section 17).
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Affiliation(s)
- Richard J Bodnar
- Department of Psychology and Neuropsychology Doctoral Sub-Program, Queens College, City University of New York, 65-30 Kissena Blvd., Flushing, NY 11367, USA.
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Lee MG, Undem BJ, Brown C, Carr MJ. Effect of nociceptin in acid-evoked cough and airway sensory nerve activation in guinea pigs. Am J Respir Crit Care Med 2006; 173:271-5. [PMID: 16239621 DOI: 10.1164/rccm.200507-1043oc] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
RATIONALE Nociceptin/orphanin FQ has been reported to inhibit capsaicin- and mechanically provoked cough in animal models, but the mechanism of this effect has not been elucidated. OBJECTIVES The objectives of this study were to determine whether nociceptin inhibits acid-evoked cough in conscious animals and to evaluate the mechanism of this effect. METHODS We tested the effect of nociceptin on acid-induced cough in conscious guinea pigs and acid-induced nerve activation in airway-specific vagal sensory neurons using calcium imaging techniques and the gramicidin-perforated patch clamp technique. MEASUREMENTS AND MAIN RESULTS Nociceptin (3 mg/kg, intraperitoneal) effectively inhibited acid-evoked cough in guinea pigs by nearly 70%. Acid (pH 5) increased intracellular free calcium in acutely dissociated vagal jugular ganglionic neurons. The acid-induced increase in intracellular calcium was inhibited by a selective transient receptor potential vanilloid-1 antagonist, 5-iodo-resiniferatoxin (1 microM, approximately 80% reduction). The inhibitory effect of 5-iodo-resiniferatoxin on acid-induced increases in calcium was mimicked by nociceptin (0.1 microM). In gramicidin-perforated patch clamp recordings on airway-specific capsaicin-sensitive jugular ganglion neurons, acid (pH 5) induced two distinct inward currents. A transient current was evoked that was inhibited by amiloride and a sustained current was evoked that was inhibited by 5-iodo-resiniferatoxin. Nociceptin selectively inhibited only the sustained component of acid-induced inward current. CONCLUSION These results indicate that the inhibitory effect of nociceptin on acid-induced cough may result from a direct inhibitory effect on peripheral C-fiber activity caused by the selective inhibition of acid-induced transient receptor potential vanilloid-1 activation.
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Affiliation(s)
- Min-Goo Lee
- Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA
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Current World Literature. Curr Opin Allergy Clin Immunol 2006; 6:67-9. [PMID: 16505615 DOI: 10.1097/01.all.0000202355.95779.17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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