title: Inhibition of Inflammation and iNOS Improves Lymphatic Function in Obesity.
abstract: Although recent studies have shown that obesity decreases lymphatic function, the cellular mechanisms regulating this response remain unknown. In the current study, we show that obesity results in perilymphatic accumulation of inflammatory cells and that local inhibition of this response with topical tacrolimus, an inhibitor of T cell differentiation, increases lymphatic vessel density, decreases perilymphatic iNOS expression, increases lymphatic vessel pumping frequency, and restores lymphatic clearance of interstitial fluid to normal levels. Although treatment of obese mice with 1400W, a selective inhibitor of iNOS, also improved lymphatic collecting vessel contractile function, it did not completely reverse lymphatic defects. Mice deficient in CD4(+) cells fed a high fat diet also gained weight relative to controls but were protected from lymphatic dysfunction. Taken together, our findings suggest that obesity-mediated lymphatic dysfunction is regulated by perilymphatic accumulation of inflammatory cells and that T cell inflammatory responses are necessary to initiate this effect.
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Torrisi
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Geoffrey E
authors.initials: GE
authors.lastname: Hespe
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Cuzzone
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Ira L
authors.initials: IL
authors.lastname: Savetsky
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Nitti
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Gardenier
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Gabriela D
authors.initials: GD
authors.lastname: García Nores
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Dawit
authors.initials: D
authors.lastname: Jowhar
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Raghu P
authors.initials: RP
authors.lastname: Kataru
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Babak J
authors.initials: BJ
authors.lastname: Mehrara
mesh_terms: D000287:Administration, Topical; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000473:pathology; D059305:Diet, High-Fat; D005247:Feeding Behavior; D007249:Inflammation / Q000150:complications* / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D042601:Lymphatic Vessels / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D009765:Obesity / Q000150:complications* / Q000201:enzymology / Q000503:physiopathology*; D016559:Tacrolimus / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D052247:Nitric Oxide Synthase Type II; D016559:Tacrolimus