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Model of facilitated platelet translocation and activation of epithelial electrogenic CI secretion during PMN transmigration:

During active inflammation, platelets are caught in the flow of PMN transmigration, resulting in platelet translocation across the apical side of mucosal epithelial cells (1). PMN and platelet-derived ATP (2) is selectively metabolized to adenosine by a two-step enzymatic reaction involving ecto-apyrase and ecto-nucleotidase (CD73) (3). Adenosine binding to apical adenosine A2B receptors (4) results in activation of electrogenic CI secretion and the paracellular movement of water (6). Such platelet/PMN - epithelial crosstalk pathway may serve as a defensive response by which mucosal surfaces are flushed from bacteria and bacterial products under inflammatory conditions.

Potential sources of hypoxia in mucosal inflammation. During episodes of inflammation, a number of factors influence the supply and demand of oxygen to the tissues, as well as influencing oxygen delivery. Noted here are edema, vasculitis and vasoconstriction, which separate epithelial cells from the blood supply and limit oxygen availability. In addition, local depletion of oxygen through processes such as the polymorphonuclear cells oxygen burst can use large quantities of oxygen and result in localized hypoxia, where red depicts normoxia and blue represents hypoxia.  

Detection of hypoxia in the mucosa. a) The in vivo evidence for hypoxia associated with inflammation (so called "inflammatory hypoxia") are provided using nitroimidazole-based dye retention in vitro and in mice. These molecules (R-NO₂) are taken into cells passively and reduced to highly reactive nitrogen intermediates (R-NO₂-[dot]). In the absence of adequate oxygen to regenerate the native compound, these intermediates react with cellular proteins to form adducts (R-NH₂), which can be visualized using labeled antibodies. b) In the colons of mice with no inflammation (control) small amounts of nitroimidazole adduct is detected along the luminal aspect of the colon (red), suggesting a degree of physiological hypoxia in the normal colon. c) During episodes of inflammation, such as seen here in a mouse model of colitis, intense and deep tissue hypoxia is prevalent, particularly in areas overlying lesions.

Representative Publications:

1. Lawrence DW, Bruyninckx WJ, Louis NA, Lublin DM, Stahl GL, Parkos CA, Colgan SP. Anti-adhesive role of apical decay-accelerating factor (DAF, CD55) in human neutrophil transmigration across mucosal epithelia. J Exp Med 2003; 198:999-1010 (Cover image).
   
2. Kong T, Eltzschig HK, Karhausen J, Colgan SP*, Shelley CS*. Leukocyte adhesion during hypoxia is mediated by HIF-1-dependent induction of 2 integrin gene expression. Proc Nat Acad Sci (USA) 2004; 101:10440-10445.
   
3. Thompson LF, Eltzschig HK, Ibla JC, Van De Wiele CJ, Resta R, Morote-Garcia JC, Colgan SP. Crucial role for ecto-5'-nucleotidase in vascular leak during hypoxia. J Exp Med 2004; 200:1395-1405.
   
4. Eltzschig HK, Abdulla P, Hoffman E, Hamilton KE, Daniels D, Schönfeld C, Löffler M, Reyes G, Duszenko M, Karhausen J, Robinson A, Westerman KA, Coe IR, and Colgan SP: HIF-1-dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia. J Exp Med 2005; 202: 1493-1505.
   
5. Khoury J, Ibla JC, Neish AS, and Colgan SP. Anti-inflammatory adaptation to hypoxia through adenosine-mediated Cullin-1 deneddylation. J Clin Invest. 2007: 117: 703-711.
   
6. Robinson AM, Keely S, Karhausen J, Gerich ME, Furuta GT, Colgan SP. Mucosal protection by hypoxia-inducible factor (HIF) prolyl hydroxylation inhibition. Gastroenterol, 2008; 134: 145-155.
   
7. Weissmuller T, Campbell EL, Rosenberger P, Scully M, Beck PL, Furuta GT, Colgan SP. PMNs facilitate translocation of platelets across human and mouse epithelium and together alter fluid homeostasis via epithelial cell-expressed ecto-NTPDases. J Clin Invest 2008; 118: 3682-93.
   
8. Frick J-S, MacManus CF, Scully M, Glover LE, Eltzschig HK, Colgan SP. Contribution of adenosine A2B receptors to inflammatory parameters of experimental colitis. J Immunol 2009: 182: 4957-4964.
   
9. Keely S, Glover LE, Weissmueller T, MacManus CF, Fillon S, Fennimore B, Colgan SP. HIF-dependent regulation of platelet activating factor receptor as a route for Gram positive bacterial translocation across epithelia. Mol Biol Cell 2010: 21, 538-546.
   

Recent Reviews:

1. Taylor CT, Colgan SP. Hypoxia and gastrointestinal disease. J Mol Med, 2008; 85: 1295-1300.
   
2. Kominsky DJ, Campbell EL, Colgan SP. Metabolic shifts in immunity and inflammation. J. Immunol, 2010: 184: 4062-4068.
   
3. Colgan, SP and Taylor CT: Hypoxia: An alarm signal during intestinal inflammation. Nature Rev. Gastroenterol and Hepatol, 2010: 7: 281-287.