TY - JOUR
T1 - Sphingosine-1-phosphate induces airway smooth muscle hyperresponsiveness and proliferation
AU - Maguire, Thomas J.A.
AU - Yung, Stephanie
AU - Ortiz-Zapater, Elena
AU - Kayode, O. Stephanie
AU - Till, Stephen
AU - Corrigan, Chris
AU - Siew, Leonard Q.C.
AU - Knock, Gregory A.
AU - Woszczek, Grzegorz
N1 - Funding Information:
This work was supported by grants from the Medical Research Council UK (grant no. G0900536 to G.W. and grant nos. MR/S009191/1 and R151002 to E.O.-Z.), Guy’s & St Thomas’ Charity (grant no. R1604 to G.W. and C.C.), and the Medical Research Council & Asthma UK Centre (grant no. G1000758 to G.W., S.T., and C.C.). The authors acknowledge support from the Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust.
Funding Information:
This work was supported by grants from the Medical Research Council UK (grant no. G0900536 to G.W. and grant nos. MR/S009191/1 and R151002 to E.O.-Z.), Guy's & St Thomas’ Charity (grant no. R1604 to G.W. and C.C.), and the Medical Research Council & Asthma UK Centre (grant no. G1000758 to G.W., S.T., and C.C.). The authors acknowledge support from the Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre award to Guy's & St Thomas’ NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust.
Publisher Copyright:
© 2023 The Authors
PY - 2023/11
Y1 - 2023/11
N2 - Background: The emerging role of sphingosine-1-phosphate (S1P) in regulating smooth muscle functions has led to the exploration of the possibility that this sphingolipid could represent a potential therapeutic target in asthma and other lung diseases. Several studies in animal surrogates have suggested a role for S1P-mediated signaling in the regulation of airway smooth muscle (ASM) contraction, airway hyperresponsiveness, and airway remodeling, but evidence from human studies is lacking. Objective: We sought to compare the responsiveness of the airways to S1P in healthy and asthmatic individuals in vivo, in isolated human airways ex vivo, and in murine airways dissected from healthy and house dust mite (HDM)-sensitized animals. Methods: Airway responsiveness was measured by spirometry during inhalation challenges and by wire myography in airways isolated from human and mouse lungs. Thymidine incorporation and calcium mobilization assays were used to study human ASM cell responses. Results: S1P did not induce contraction of airways isolated from healthy and HDM-exposed mice, nor in human airways. Similarly, there was no airway constriction observed in healthy and asthmatic subjects in response to increasing concentrations of inhaled S1P. However, a 30-minute exposure to S1P induced a significant concentration-dependent enhancement of airway reactivity to methacholine and to histamine in murine and human airways, respectively. HDM-sensitized mice demonstrated a significant increase in methacholine responsiveness, which was not further enhanced by S1P treatment. S1P also concentration-dependently enhanced proliferation of human ASM cells, an effect mediated through S1P receptor type 2, as shown by selective antagonism and S1P receptor type 2 small-interfering RNA knockdown. Conclusions: Our data suggest that S1P released locally into the airways may be involved in the regulation of ASM hyperresponsiveness and hyperplasia, defining a novel target for future therapies.
AB - Background: The emerging role of sphingosine-1-phosphate (S1P) in regulating smooth muscle functions has led to the exploration of the possibility that this sphingolipid could represent a potential therapeutic target in asthma and other lung diseases. Several studies in animal surrogates have suggested a role for S1P-mediated signaling in the regulation of airway smooth muscle (ASM) contraction, airway hyperresponsiveness, and airway remodeling, but evidence from human studies is lacking. Objective: We sought to compare the responsiveness of the airways to S1P in healthy and asthmatic individuals in vivo, in isolated human airways ex vivo, and in murine airways dissected from healthy and house dust mite (HDM)-sensitized animals. Methods: Airway responsiveness was measured by spirometry during inhalation challenges and by wire myography in airways isolated from human and mouse lungs. Thymidine incorporation and calcium mobilization assays were used to study human ASM cell responses. Results: S1P did not induce contraction of airways isolated from healthy and HDM-exposed mice, nor in human airways. Similarly, there was no airway constriction observed in healthy and asthmatic subjects in response to increasing concentrations of inhaled S1P. However, a 30-minute exposure to S1P induced a significant concentration-dependent enhancement of airway reactivity to methacholine and to histamine in murine and human airways, respectively. HDM-sensitized mice demonstrated a significant increase in methacholine responsiveness, which was not further enhanced by S1P treatment. S1P also concentration-dependently enhanced proliferation of human ASM cells, an effect mediated through S1P receptor type 2, as shown by selective antagonism and S1P receptor type 2 small-interfering RNA knockdown. Conclusions: Our data suggest that S1P released locally into the airways may be involved in the regulation of ASM hyperresponsiveness and hyperplasia, defining a novel target for future therapies.
KW - airway contraction
KW - airway smooth muscle
KW - Asthma
KW - sphingolipids
UR - http://www.scopus.com/inward/record.url?scp=85166909101&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2023.05.028
DO - 10.1016/j.jaci.2023.05.028
M3 - Article
C2 - 37474025
AN - SCOPUS:85166909101
SN - 0091-6749
VL - 152
SP - 1131-1140.e6
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 5
ER -