S1P‐induced airway smooth muscle hyperresponsiveness and lung inflammation in vivo: molecular and cellular mechanisms

Abstract

BACKGROUND AND PURPOSESphingosine-1-phosphate (S1P) has been shown to be involved in the asthmatic disease as well in preclinical mouse experimental models of this disease. The aim of this study was to understand the mechanism(s) underlying S1P effects on the lung. EXPERIMENTAL APPROACHBALB/c, mast cell-deficient and Nude mice were injected with S1P (s.c.) on days 0 and 7. Functional, molecular and cellular studies were performed. KEY RESULTSS1P administration to BALB/c mice increased airway smooth muscle reactivity, mucus production, PGD2, IgE, IL-4 and IL-13 release. These features were associated to a higher recruitment of mast cells to the lung. Mast cell-deficient Kit W-sh/W-sh mice injected with S1P did not display airway smooth muscle hyper-reactivity. However, lung inflammation and IgE production were still present. Treatment in vivo with the anti-CD23 antibody B3B4, which blocks IgE production, inhibited both S1P-induced airway smooth muscle reactivity in vitro and lung inflammation. S1P administration to Nude mice did not elicit airway smooth muscle hyper-reactivity and lung inflammation. Naïve (untreated) mice subjected to the adoptive transfer of CD4+ T-cells harvested from S1P-treated mice presented all the features elicited by S1P in the lung. CONCLUSIONS AND IMPLICATIONSS1P triggers a cascade of events that sequentially involves T-cells, IgE and mast cells reproducing several asthma-like features. This model may represent a useful tool for defining the role of S1P in the mechanism of action of currently-used drugs as well as in the development of new therapeutic approaches for asthma-like diseases. AbbreviationsCFSE, carboxyfluoresceindiacetate, succinimidyl ester; FcεRI, high affinity IgE receptor; H&E, haematoxylin and eosin; PAS, periodic acid/Alcian blue/Schiff; S1P, sphingosine-1-phosphate; SPK, sphingosine kinase BJP British Journal of Pharmacology

Exploration of the Sphingolipid Metabolite, Sphingosine-1-phosphate and Sphingosine, as Novel Biomarkers for Aspirin-exacerbated Respiratory Disease

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“…An in vivo study has reported that S1P treatment induced secretion of T-helper 2 lymphocyte (Th2) and Th17 cytokines, such as interleukin-4 (IL-4) and IL-17, respectively10. S1P has also been associated with methacholine-induced airway hyperreactivity, bronchoconstriction and airway remodeling by targeting genes regulating cell proliferation41112.…”

MicroRNA-146a expression inhibits the proliferation and promotes the apoptosis of bronchial smooth muscle cells in asthma by directly targeting the epidermal growth factor receptor

“…These cytokines induce the attachment of mast cells to BSMCs, promote the survival and proliferation of mast cells, facilitate the accumulation of inflammatory substances, thicken smooth muscles and lead to airway hyperreactivity. Previous investigations also demonstrated that attachment of T lymphocytes to BSMCs induces DNA synthesis in the BSMCs, which enhances their proliferation (6,7). Enhanced proliferation and decreased apoptosis of BSMCs may result in airway hyperreactivity (6,8).…”

Functional contribution of sphingosine‐1‐phosphate to airway pathology in cigarette smoke‐exposed mice

“…In the last years, a critical role for the Sph‐K/S1P pathway in the control of airway function and pulmonary inflammation has been demonstrated (Price et al, ; Roviezzo et al, ; Roviezzo et al, ; Roviezzo et al, ; Roviezzo et al, ; Roviezzo et al, ). Compelling evidence from rodent models suggests that S1P signalling represents feasible therapeutic target(s) for lung diseases (Arish, Alaidarous, Ali, Akhter, & Rub, ; Ebenezer, Fu, & Natarajan, ).…”

“…In particular, the inhibition of S1P biosynthesis reduces allergen‐induced asthma‐like features (Price et al, ; Roviezzo et al, ),while the administration of S1P worsens antigen‐induced airway inflammation (Chiba, Takeuchi, Sakai, & Misawa, ) and airway hyperresponsiveness (AHR). Furthermore, the systemic administration of S1P, without additional adjuvant factors, triggers in the mouse a disease closely mimicking several features of severe asthma such as AHR, pulmonary inflammation, high circulating levels of IgE, and a predominance of CD4 + T cell‐derived IL‐4 (Roviezzo et al, ). This finds a match in the human disease, where S1P levels significantly increase in bronchoalveolar lavage of asthmatic patients following segmental allergen challenge and correlate to pulmonary inflammation (Ammit et al, ).…”