Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
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Query: UNIPROT:P15088 (
mast cell
)
14,925
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Mast cell-airway smooth muscle (ASM) interactions play a major role in the immunoglobulin (Ig)E- dependent bronchoconstriction seen in asthma but less is known about IgE-independent mechanisms of
mast cell
activation.
Transient receptor potential cation channel, subfamily V, member 4
(
TRPV4
) activation causes contraction of human ASM
via
the release of cysteinyl leukotrienes (cysLTs) but the mechanism is unknown. The objective of the present study was to investigate a role for IgE-independent,
mast cell
-ASM interaction in
TRPV4
-induced bronchospasm.Bronchoconstriction was measured in anaesthetised guinea pigs and contraction of human and guinea-pig airway tissue assessed using isometric tension measurements. Increases in intracellular [Ca
2+
] were imaged using the Ca
2+
-sensitive dye FURA2, and time-lapse ptychography was utilised as a surrogate for contraction of ASM cells.The
TRPV4
agonist GSK1016790A caused contraction
in vivo
in the guinea pig, and in human and guinea-pig tracheal tissue, which was inhibited by the
TRPV4
antagonist GSK2193874. GSK1016790A increased [Ca
2+
]
i
and released ATP in human ASM cells without causing contraction.
TRPV4
and ATP evoked contraction in isolated tracheal tissue but co-culture experiments indicated a requirement for human lung mast cells. Expression profiling and pharmacological studies demonstrated that
mast cell
activation was dependent upon ATP activating the P2X4 receptor. Trypsin was shown to evoke contraction of tracheal tissue
via
activation of PAR-2-
TRPV4
-ATP-cysLT axis indicating the potential disease relevance of this signalling pathway.
TRPV4
activation increases [Ca
2+
]
i
and releases ATP from ASM cells triggering P2X4-dependent release of cysLTs from mast cells resulting in ASM contraction. This study delineates a novel
mast cell
-ASM interaction and
TRPV4
as a driver of IgE-independent
mast cell
-dependent bronchospasm.
...
PMID:Novel airway smooth muscle-mast cell interactions and a role for the TRPV4-ATP axis in non-atopic asthma. 3261 49
