|Smith, C wayne|
Submitted to: Blood
Publication Type: Peer reviewed journal
Publication Acceptance Date: 4/2/2001
Publication Date: 8/1/2001
Citation: Collins, R.G., Jung, U., Ramirez, M., Bullard, D.C., Hicks, M.J., Smith, W.C., Ley, K., Beaudet, A.L. 2001. Dermal and pulmonary inflammatory disease in e-selectin and p-selectin double-null mice is reduced in triple-selectin-null mice. Blood. 98(3):727-735. Interpretive Summary: Inflammation results when certain proteins are produced on the surface of blood vessels, for example, following exposure to toxins present in the gastrointestinal track. This paper discusses the effect of genetic engineering to remove certain of these proteins.
Technical Abstract: In the initial phase of an inflammatory response, leukocytes marginate and roll along the endothelial surface as a result of adhesive interactions between molecules on the endothelial cells and leukocytes. To evaluate the role of the 3 selectins (E, L, and P) in leukocyte rolling and emigration, a null mutation for L-selectin was introduced into previously described embryonic stem cells with null mutations in the genes for both E-selectin and P-selectin (E/P double mutants) to produce triple-selectin-null mice (E-selectin, L-selectin, and P-selectin [E/L/P] triple mutants). Triple-selectin homozygous mutant mice are viable and fertile and only rarely develop the severe mucocutaneous infections or pulmonary inflammation characteristic of E/P double-mutant mice. Surface expression of L-selectin was undetectable in triple-mutant mice on fluorescence-activated cell-sorter analysis of peripheral neutrophils. Pathological studies revealed moderate cervical lymphadenopathy and lymphoplasmacytic infiltrate, but these were less extensive than in E/P double-mutant mice. Neutrophil emigration during thioglycolate-induced peritonitis was significantly reduced at 4, 8, and 24 hours (35%, 65%, and 46% of wild-type values, respectively). Intravital microscopy of the cremaster muscle revealed almost no rolling at times up to 6 hours after exteriorization, with or without addition of tumor necrosis factor alpha. The small amount of residual rolling was dependent on alpha(4)-integrin. The occurrence of skin and pulmonary disease in E/P double-mutant mice but not E/L/P triple-mutant mice suggests that deficiency of L-selectin alters the inflammatory response in E/P mutants.