title: Increased interstitial protein because of impaired lymph drainage does not induce fibrosis and inflammation in lymphedema.
abstract: OBJECTIVE
  The pathophysiology of lymphedema is incompletely understood. We asked how transcapillary fluid balance parameters and lymph flow are affected in a transgenic mouse model of primary lymphedema, which due to an inhibition of vascular endothelial growth factor receptor-3 (VEGFR-3) signaling lacks dermal lymphatics, and whether protein accumulation in the interstitium occurring in lymphedema results in inflammation.
  
  
  RESULTS
  As estimated using a new optical-imaging technique, we found that this signaling defect resulted in lymph drainage in hind limb skin of K14-VEGFR-3-Ig mice that was 34% of the corresponding value in wild-type. The interstitial fluid pressure and tissue fluid volumes were significantly increased in the areas of visible swelling only, whereas the colloid osmotic pressure in plasma, and thus the colloid osmotic pressure gradient, was reduced compared to wild-type mice. An acute volume load resulted in an exaggerated interstitial fluid pressure response in transgenic mice. There was no accumulation of collagen or lipid in skin, suggesting that chronic edema presented in the K14-VEGFR-3-Ig mouse was not sufficient to induce changes in tissue composition. Proinflammatory cytokines (interleukin-2, interleukin-6, interleukin-12) in subcutaneous interstitial fluid and macrophage infiltration in skin of the paw were lower, whereas the monocyte/macrophage cell fraction in blood and spleen was higher in transgenic compared with wild-type mice.
  
  
  CONCLUSIONS
  Our data suggest that a high interstitial protein concentration and longstanding edema is not sufficient to induce fibrosis and inflammation characteristic for the human condition and may have implications for our understanding of the pathophysiology of this condition.
authors.affiliation: Department of Biomedicine, University of Bergen, Norway.
authors.forename: C E
authors.initials: CE
authors.lastname: Markhus
authors.forename: T V
authors.initials: TV
authors.lastname: Karlsen
authors.forename: Marek
authors.initials: M
authors.lastname: Wagner
authors.forename: M
authors.initials: M
authors.lastname: Wagner
authors.forename: Ø S
authors.initials: ØS
authors.lastname: Svendsen
authors.forename: O
authors.initials: O
authors.lastname: Tenstad
authors.forename: K
authors.initials: K
authors.lastname: Alitalo
authors.forename: H
authors.initials: H
authors.lastname: Wiig
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D017449:Dermatitis, Allergic Contact / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D045604:Extracellular Fluid / Q000378:metabolism*; D005260:Female; D005355:Fibrosis; D005838:Genotype; D018836:Inflammation Mediators / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D042601:Lymphatic Vessels / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008209:Lymphedema / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009997:Osmotic Pressure; D010539:Permeability; D010641:Phenotype; D011506:Proteins / Q000378:metabolism; D012709:Serum Albumin / Q000378:metabolism; D012867:Skin / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism; D014883:Water-Electrolyte Imbalance / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D018836:Inflammation Mediators; D007376:Interleukin-2; D015850:Interleukin-6; D011506:Proteins; D012709:Serum Albumin; D018664:Interleukin-12; D003094:Collagen; D040321:Vascular Endothelial Growth Factor Receptor-3