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Epithelial exposure to hypoxia modulates neutrophil transepithelial migration
S P Colgan1, A L Dzus, C A Parkos
1Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Boston, Massachusetts, USA.
The Journal of Experimental Medicine
|September 1, 1996
Summary
Hypoxia/reoxygenation significantly increases polymorphonuclear leukocyte (PMN) migration across intestinal epithelial cells. This process, mediated by IL-8 and integrins, highlights new crosstalk in intestinal disease pathogenesis.
Area of Science:
- Gastroenterology
- Immunology
- Cell Biology
Background:
- Polymorphonuclear leukocytes (PMN) are implicated in intestinal diseases like necrotizing enterocolitis and reperfusion injury.
- Tissue hypoxia is a suspected mediator in these PMN-induced intestinal pathologies.
- The interaction between intestinal epithelia and PMNs under hypoxic conditions is not well understood.
Purpose of the Study:
- To investigate the effect of hypoxia/reoxygenation (H/R) on PMN transepithelial migration across intestinal epithelial cells.
- To elucidate the molecular mechanisms underlying H/R-modulated PMN-epithelial interactions.
Main Methods:
- T84 human intestinal crypt cell monolayers were exposed to varying degrees of hypoxia (2-21% O2) for up to 72 hours.
- PMN transmigration across monolayers was assessed under H/R conditions, driven by a chemotactic peptide gradient.
- Involvement of protein synthesis, beta 2 integrin CD11b/18, CD47, and interleukin-8 (IL-8) was evaluated using inhibitors, antibodies, and antisense oligonucleotides.
Main Results:
- H/R significantly increased PMN transmigration in a dose- and time-dependent manner (up to 3.5-fold increase at 2% O2 for 48h).
- H/R did not induce epithelial toxicity or compromise barrier function.
- Increased PMN transmigration was dependent on protein synthesis and inhibited by antibodies against CD11b/18 and CD47.
- Hypoxia stimulated epithelial IL-8 production and release, which was associated with the epithelial matrix.
- IL-8 antisense oligonucleotides reduced PMN association with the monolayer but not transmigration, suggesting a role in PMN recruitment.
Conclusions:
- Hypoxia/reoxygenation is a potent stimulus that enhances PMN migration across intestinal epithelia.
- This H/R-induced effect involves protein synthesis, epithelial IL-8 release, and PMN adhesion molecules CD11b/18 and CD47.
- Novel biochemical crosstalk between epithelia and PMNs is established under H/R conditions, relevant to intestinal disease pathogenesis.