Development of new therapeutic strategies in the control of asthma

Asthma is a chronic inflammatory disease of the airways which affects more than 300 million people worldwide. Asthma treatment aims to improve patients' quality of life reducing airway inflammation and restoring respiratory function. Most patients can achieve good asthma control, but some patients do not. It seems increasingly evident that asthma is not a single and local disease but has different phenotypes and develops as a systemic disease, that could explain the non-constant therapeutic response. In light of this, the aim of this thesis project was to clarify on the one hand the involvement of sphingolipids such as sphingosine-1-phosphate (S1P) in the pathogenesis of asthma and on the other hand to clarify the contribution of sex hormones and vascular function to symptoms and exacerbations development. The results obtained demonstrate: • a key role SPK/S1P pathway in the development of bronchial hyperactivity as well as airway remodeling associated with exposure to cigarette smoke; • that sex hormones cause a sex dimorphism in bronchial hyperreactivity following allergen sensitization in favor of females. This sex dimorphism well correlate with leukotrienes upregulation in the lung; • that there is a strong and specific link between bronchial and vascular function and involvement of the pulmonary artery in determining the systemic impact of the disease. In conclusion, the data obtained confirm the complexity of asthmatic pathology and its relationship with other pulmonary and systemic inflammatory pathologies

Lack of Ecto-5'-Nucleotidase Protects Sensitized Mice against Allergen Challenge

Ecto-5'-nucleotidase (CD73), the ectoenzyme that together with CD39 is responsible for extracellular ATP hydrolysis and adenosine accumulation, regulates immune/inflammatory processes by controlling innate and acquired immunity cell functions. We previously demonstrated that CD73 is required for the assessment of a controlled allergic sensitization, in mice. Here, we evaluated the response to aerosolized allergen of female-sensitized mice lacking CD73 in comparison with their wild type counterpart. Results obtained show, in mice lacking CD73, the absence of airway hyperreactivity in response to an allergen challenge, paralleled by reduced airway CD23+B cells and IL4+T cells pulmonary accumulation together with reduced mast cells accumulation and degranulation. Our findings indicate CD73 as a potential therapeutic target for allergic asthma

Antagonizing S1P3 Receptor with Cell-Penetrating Pepducins in Skeletal Muscle Fibrosis

S1P is the final product of sphingolipid metabolism, which interacts with five widely expressed GPCRs (S1P1-5). Increasing numbers of studies have indicated the importance of S1P3 in various pathophysiological processes. Recently, we have identified a pepducin (compound KRX-725-II) acting as an S1P3 receptor antagonist. Here, aiming to optimize the activity and selectivity profile of the described compound, we have synthesized a series of derivatives in which Tyr, in position 4, has been substituted with several natural aromatic and unnatural aromatic and non-aromatic amino acids. All the compounds were evaluated for their ability to inhibit vascular relaxation induced by KRX-725 (as S1P3 selective pepducin agonist) and KRX-722 (an S1P1-selective pepducin agonist). Those selective towards S1P3 (compounds V and VII) were also evaluated for their ability to inhibit skeletal muscle fibrosis. Finally, molecular dynamics simulations were performed to derive information on the preferred conformations of selective and unselective antagonists

Beneficial Effects of Astragalus membranaceus (Fisch.) Bunge Extract in Controlling Inflammatory Response and Preventing Asthma Features

Astragalus membranaceus (Fisch.) Bunge root is used as herbal medicine for its immunomodulating activities in Chinese medicine. Recently, beneficial properties of A. membranaceus on allergic diseases have been proposed. Here we investigated the role of a commercial extract of A. membranaceus, standardized to 16% polysaccharides, in regulating the immune-inflammatory response in vitro and in vivo and its therapeutic application in asthma. A. membranaceus extract inhibited prostaglandin E2 and leukotriene C4 production in stimulated J774 and peritoneal macrophages, respectively. The extract also reduced interlukin-1β, tumor necrosis factor-α, and nitrite production, affecting inducible nitric oxide synthase expression. In vivo experiments confirmed the anti-inflammatory properties of A. membranaceus, as evident by a reduction in zymosan-induced peritoneal cellular infiltration and pro-inflammatory mediator production. The efficacy of A. membranaceus extract in modulating the immune response was confirmed in a model of allergic airway inflammation. Extracts improve lung function by inhibiting airway hyperresponsiveness, airway remodeling, and fibrosis. Its anti-asthmatic effects were further sustained by inhibition of the sensitization process, as indicated by a reduction of ovalbumin-induced IgE levels and the mounting of a Th2 immune response. In conclusion, our data demonstrate the anti-inflammatory properties of the commercial extract of A. membranaceus and its beneficial effects on asthma feature development

Caspase-11 and AIM2 inflammasome are involved in smoking-induced COPD and lung adenocarcinoma

Cigarette smoking is the leading risk factor for COPD and lung cancer establishment. Epidemiologically, COPD patients are 6.35 times more likely to develop lung cancer. To mimic COPD, we exposed mice to nose-only cigarette smoke and used human samples of lung adenocarcinoma patients according to the smoking and COPD status. Smoking C57Bl/6N mice had higher enlargement of alveoli, deposition of collagen and mucus production, associated to the release of IL-1-like cytokines, such as IL-1α and IL-1β at early time points and IL-18 at later time points. AIM2 expression was higher in lung recruited dendritic cells and macrophages in smoking mice, associated to the activation of caspase-11, rather than caspase-1. In support,129Sv mice, which are dysfunctional for caspase-11, had lower collagen deposition and mucus production, associated to lower release of IL-1-like and fibrotic TGFβ. Interestingly, higher expression of AIM2 in non-cancerous tissue of smoking COPD adenocarcinoma patients was correlated to a higher hazard ratio of poor survival rate than in patients who presented lower levels of AIM2. We found that AIM2 inflammasome is at the crossroad between COPD and lung cancer in that its higher presence is correlated to lower survival rate of smoking COPD adenocarcinoma patients

The inhibition of caspase-1- does not revert particulate matter (PM)-induced lung immunesuppression in mice

Background: Air pollution is becoming a threatening issue for human health. Many epidemiological studies relate air pollution index to adverse effects in terms of disease incidence and/or disease exacerbation. In our previous studies, we found air pollutants can induce the release of pro-inflammatory cytokines from human peripheral blood cells. To better understand, the effects of air pollution in the lung, we took advantage of an animal model. Experimental Approach: Mice were intratracheally and daily exposed to urban collected particulate matter (PM, PM10, and PM1) and to the sub-micrometric carbonaceous component, Soot. Results: We found that PM10, PM1, and Soot promoted lung inflammation associated to higher bronchial responsiveness and lower dilation together with an immunosuppressive lung environment, characterized by tolerogenic dendritic cells (DCs), macrophages and myeloid -derived suppressor cells (MDSCs), the latter two Arginase I positive. In support, higher recruitment of Treg associated to higher levels of IL-10 were detected in the lung of PM10, PM1, and Soot treated mice. This effect was not abolished by the administration of a caspase-1 inhibitor, Ac-Y-VAD, implying that the canonical inflammasome complex was not associated to PMx-induced lung immunosuppression in mice. Conclusion: Our study proves that PM exposure leads to an immunosuppressive lung environment in a caspase-1-independent manner, paving the way to understand the molecular and cellular mechanism/s underlying the establishment of some respiratory disorders according to the exposure to air pollution

Understanding the role of the gut microbiome in gastrointestinal cancer: A review

Copyright © 2023 Ağagündüz, Cocozza, Cemali, Bayazıt, Nanì, Cerqua, Morgillo, Saygılı, Berni Canani, Amero and Capasso.Gastrointestinal cancer represents one of the most diagnosed types of cancer. Cancer is a genetic and multifactorial disease, influenced by the host and environmental factors. It has been stated that 20% of cancer is caused by microorganisms such as Helicobacter pylori, hepatitis B and C virus, and human papillomavirus. In addition to these well-known microorganisms associated with cancer, it has been shown differences in the composition of the microbiota between healthy individuals and cancer patients. Some studies have suggested the existence of the selected microorganisms and their metabolites that can promote or inhibit tumorigenesis via some mechanisms. Recent findings have shown that gut microbiome and their metabolites can act as cancer promotors or inhibitors. It has been shown that gastrointestinal cancer can be caused by a dysregulation of the expression of non-coding RNA (ncRNA) through the gut microbiome. This review will summarize the latest reports regarding the relationship among gut microbiome, ncRNAs, and gastrointestinal cancer. The potential applications of diagnosing and cancer treatments will be discussed

Leukotriene-mediated sex dimorphism in murine asthma-like features during allergen sensitization

The incidence and severity of asthma preponderate in women versus men. Leukotrienes (LTs) are lipid mediators involved in asthma pathogenesis, and sex disparities in LT biosynthesis and anti-LT pharmacology in inflammation have recently emerged. Here, we report on sex dimorphism in LT production during allergen sensitization and its correlation to lung function. While high plasma levels of IgE, as sensitization index, were elevated in both sexes, LT levels increased only in lungs of female ovalbumin-sensitized BALB/c mice. Sex-dependent elevated LT levels strictly correlated to an enhanced airway hyperreactivity, pulmonary inflammation and mast cell infiltration/activation in female mice. Importantly, this sex bias was coupled to superior therapeutic efficacy of different types of clinically used LT modifiers like zileuton, MK886 and montelukast in female animals. Our findings reveal sex-dependent LT production as a basic mechanism of sex dimorphism in allergic asthma, and suggest that women might benefit more from anti-LT asthma therapy

FUNCTIONAL CONTRIBUTION OF SPHINGOSINE-1-PHOSPHATE TO AIRWAY PATHOLOGY IN CIGARETTE SMOKE EXPOSED MICE

Background and Purpose: A critical role for sphingosine kinase/sphingosine-1-phosphate (S1P) pathway in the control of airway function has been demonstrated in respiratory diseases. Here, we address S1P contribution in a mouse model of mild chronic obstructive pulmonary disease (COPD). Experimental Approach: C57BL/6J mice have been exposed to room air or cigarette smoke up to 11 months and killed at different time points. Functional and molecular studies have been performed. Key Results: Cigarette smoke caused emphysematous changes throughout the lung parenchyma coupled to a progressive collagen deposition in both peribronchiolar and peribronchial areas. The high and low airways showed an increased reactivity to cholinergic stimulation and α-smooth muscle actin overexpression. Similarly, an increase in airway reactivity and lung resistances following S1P challenge occurred in smoking mice. A high expression of S1P, Sph-K2, and S1P receptors (S1P2 and S1P3) has been detected in the lung of smoking mice. Sphingosine kinases inhibition reversed the increased cholinergic response in airways of smoking mice. Conclusions and Implications: S1P signalling up-regulation follows the disease progression in smoking mice and is involved in the development of airway hyperresponsiveness. Our study defines a therapeutic potential for S1P inhibitors in management of airways hyperresponsiveness associated to emphysema in smokers with both asthma and COPD