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Prolyl Hydroxylase Inhibition Attenuates Mast Cell Degranulation During Systemic Hypoxia Via Upregulation of Heme Oxygenase‐1
Author(s) -
Wood John G.,
Moncure Michael,
Thomas James H.,
Holloway Naomi B.,
Gonzalez Norberto C.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1150.7
Subject(s) - degranulation , heme oxygenase , downregulation and upregulation , mast cell , intravital microscopy , chemistry , hypoxia (environmental) , inflammation , microcirculation , medicine , endocrinology , immunology , heme , enzyme , biochemistry , receptor , organic chemistry , oxygen , gene
Acute systemic hypoxia (Hx) causes mast cell degranulation and increased leukocyte adherence in post‐capillary venules of rats. When animals are chronically hypoxic, microvascular inflammation resolves in part due to upregulation of heme oxygenase‐1 (HO‐1), which prevents mast cell activation. Inhibition of prolyl hydroxylase (PHD) increases hypoxia‐inducible factor‐1 (HIF‐1) levels, which promotes HO‐1 expression. Objective Our goal was to evaluate whether inhibition of PHD attenuated Hx‐induced mast cell degranulation, and if upregulation of HO‐1 was involved. Methods Intravital microscopy was used to measure mast cell degranulation and leukocyte adherence in mesenteric venules of anesthetized rats. The PHD inhibitor ethyl dihydroxybenzoate (EDHB) was injected s.c. to rats 24 hrs prior to experiments. Hx was produced in rats breathing 10% O 2 . Results Hx caused mast cell degranulation and increased leukocyte adherence in the mesenteric microcirculation of vehicle‐ but not EDHB‐treated rats. Superfusion of the mesentery with the HO‐1 inhibitor zinc protoporphyrin caused a significant increase in mast cell degranulation and leukocyte adherence during Hx in EDHB‐ but not in vehicle‐treated rats. Conclusion Inhibition of PHD reduces Hx‐induced mast cell degranulation and leukocyte adherence in part through HO‐1 upregulation, which is consistent with a HIF‐1‐dependent mechanism.