1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Physiology
  4. Volume 80, 2018
  5. Article

Annual Review of Physiology

Volume 80, 2018

Lymphatic Dysfunction, Leukotrienes, and Lymphedema

Abstract

The lymphatic system is essential for the maintenance of tissue fluid homeostasis, gastrointestinal lipid absorption, and immune trafficking. Whereas lymphatic regeneration occurs physiologically in wound healing and tissue repair, pathological lymphangiogenesis has been implicated in a number of chronic diseases such as lymphedema, atherosclerosis, and cancer. Insight into the regulatory mechanisms of lymphangiogenesis and the manner in which uncontrolled inflammation promotes lymphatic dysfunction is urgently needed to guide the development of novel therapeutics: These would be designed to reverse lymphatic dysfunction, either primary or acquired. Recent investigation has demonstrated the mechanistic role of leukotriene B (LTB) in the molecular pathogenesis of lymphedema. LTB, a product of the innate immune response, is a constituent of the eicosanoid inflammatory mediator family of molecules that promote both physiological and pathological inflammation. Here we provide an overview of lymphatic development, the pathophysiology of lymphedema, and the role of leukotrienes in lymphedema pathogenesis.

Keyword(s): 5-lipoxygenase, leukotriene B4, lymphedema
Loading

Article metrics loading...

/content/journals/10.1146/annurev-physiol-022516-034008
2018-02-10
2024-05-01
Loading full text...

Full text loading...

/deliver/fulltext/physiol/80/1/annurev-physiol-022516-034008.html?itemId=/content/journals/10.1146/annurev-physiol-022516-034008&mimeType=html&fmt=ahah

Literature Cited

  1. Peters-Golden M, Henderson WR Jr.. 1.  2007. Leukotrienes. N. Engl. J. Med. 357:1841–54 [Google Scholar]
  2. Radmark OP.2.  2000. The molecular biology and regulation of 5-lipoxygenase. Am. J. Respir. Crit. Care Med. 161:S11–15 [Google Scholar]
  3. Peters-Golden M, Brock TG. 3.  2001. Intracellular compartmentalization of leukotriene synthesis: unexpected nuclear secrets. FEBS Lett 487:323–26 [Google Scholar]
  4. Luo M, Jones SM, Peters-Golden M, Brock TG. 4.  2003. Nuclear localization of 5-lipoxygenase as a determinant of leukotriene B4 synthetic capacity. PNAS 100:12165–70 [Google Scholar]
  5. Rouzer CA, Samuelsson B. 5.  1985. On the nature of the 5-lipoxygenase reaction in human leukocytes: enzyme purification and requirement for multiple stimulatory factors. PNAS 82:6040–44 [Google Scholar]
  6. Percival MD, Denis D, Riendeau D, Gresser MJ. 6.  1992. Investigation of the mechanism of non-turnover-dependent inactivation of purified human 5-lipoxygenase. Inactivation by H2O2 and inhibition by metal ions. Eur. J. Biochem. 210:109–17 [Google Scholar]
  7. Hanaka H, Shimizu T, Izumi T. 7.  2005. Stress-induced nuclear export of 5-lipoxygenase. Biochem. Biophys. Res. Commun. 338:111–16 [Google Scholar]
  8. Flamand N, Luo M, Peters-Golden M, Brock TG. 8.  2009. Phosphorylation of serine 271 on 5-lipoxygenase and its role in nuclear export. J. Biol. Chem. 284:306–13 [Google Scholar]
  9. Luo M, Jones SM, Flamand N, Aronoff DM, Peters-Golden M, Brock TG. 9.  2005. Phosphorylation by protein kinase A inhibits nuclear import of 5-lipoxygenase. J. Biol. Chem. 280:40609–16 [Google Scholar]
  10. Dixon RA, Diehl RE, Opas E, Rands E, Vickers PJ. 10.  et al. 1990. Requirement of a 5-lipoxygenase-activating protein for leukotriene synthesis. Nature 343:282–84 [Google Scholar]
  11. Abramovitz M, Wong E, Cox ME, Richardson CD, Li C, Vickers PJ. 11.  1993. 5-lipoxygenase-activating protein stimulates the utilization of arachidonic acid by 5-lipoxygenase. Eur. J. Biochem. 215:105–11 [Google Scholar]
  12. Peters-Golden M, Brock TG. 12.  2003. 5-lipoxygenase and FLAP. Prostaglandins Leukot. Essent. Fatty Acids 69:99–109 [Google Scholar]
  13. Haeggstrom JZ.13.  2000. Structure, function, and regulation of leukotriene A4 hydrolase. Am. J. Respir. Crit. Care Med. 161:S25–31 [Google Scholar]
  14. Jakschik BA, Kuo CG. 14.  1983. Characterization of leukotriene A4 and B4 biosynthesis. Prostaglandins 25:767–82 [Google Scholar]
  15. Zhou S, Stark JM, Leikauf GD. 15.  1995. Leukotriene B4 formation: human neutrophil-airway epithelial cell interactions. J. Appl. Physiol. 78:1396–403 [Google Scholar]
  16. Haeggstrom JZ, Wetterholm A, Vallee BL, Samuelsson B. 16.  1990. Leukotriene A4 hydrolase: an epoxide hydrolase with peptidase activity. Biochem. Biophys. Res. Commun. 173:431–37 [Google Scholar]
  17. Murphy RC, Gijon MA. 17.  2007. Biosynthesis and metabolism of leukotrienes. Biochem. J. 405:379–95 [Google Scholar]
  18. Lam BK.18.  2003. Leukotriene C4 synthase. Prostaglandins Leukot. Essent. Fatty Acids 69:111–16 [Google Scholar]
  19. Maclouf JA, Murphy RC. 19.  1988. Transcellular metabolism of neutrophil-derived leukotriene A4 by human platelets. A potential cellular source of leukotriene C4. J. Biol. Chem. 263:174–81 [Google Scholar]
  20. Lynch KR, O'Neill GP, Liu Q, Im DS, Sawyer N. 20.  et al. 1999. Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature 399:789–93 [Google Scholar]
  21. Hui Y, Cheng Y, Smalera I, Jian W, Goldhahn L. 21.  et al. 2004. Directed vascular expression of human cysteinyl leukotriene 2 receptor modulates endothelial permeability and systemic blood pressure. Circulation 110:3360–66 [Google Scholar]
  22. Beller TC, Maekawa A, Friend DS, Austen KF, Kanaoka Y. 22.  2004. Targeted gene disruption reveals the role of the cysteinyl leukotriene 2 receptor in increased vascular permeability and in bleomycin-induced pulmonary fibrosis in mice. J. Biol. Chem. 279:46129–34 [Google Scholar]
  23. Kanaoka Y, Boyce JA. 23.  2004. Cysteinyl leukotrienes and their receptors: cellular distribution and function in immune and inflammatory responses. J. Immunol. 173:1503–10 [Google Scholar]
  24. Yokomizo T, Kato K, Terawaki K, Izumi T, Shimizu T. 24.  2000. A second leukotriene B4 receptor, BLT2: a new therapeutic target in inflammation and immunological disorders. J. Exp. Med. 192:421–32 [Google Scholar]
  25. Afonso PV, Janka-Junttila M, Lee YJ, McCann CP, Oliver CM. 25.  et al. 2012. LTB4 is a signal-relay molecule during neutrophil chemotaxis. Dev. Cell 22:1079–91 [Google Scholar]
  26. Lammermann T, Afonso PV, Angermann BR, Wang JM, Kastenmüller W. 26.  et al. 2013. Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo. . Nature 498:371–75 [Google Scholar]
  27. McNelis JC, Olefsky JM. 27.  2014. Macrophages, immunity, and metabolic disease. Immunity 41:36–48 [Google Scholar]
  28. Li P, Oh DY, Bandyopadhyay G, Lagakos WS, Talukdar S. 28.  et al. 2015. LTB4 promotes insulin resistance in obese mice by acting on macrophages, hepatocytes and myocytes. Nat. Med. 21:239–47 [Google Scholar]
  29. Subbarao K, Jala VR, Mathis S, Suttles J, Zacharias W. 29.  et al. 2004. Role of leukotriene B4 receptors in the development of atherosclerosis: potential mechanisms. Arterioscler. Thromb. Vasc. Biol. 24:369–75 [Google Scholar]
  30. Goodarzi K, Goodarzi M, Tager AM, Luster AD, von Andrian UH. 30.  2003. Leukotriene B4 and BLT1 control cytotoxic effector T cell recruitment to inflamed tissues. Nat. Immunol. 4:965–73 [Google Scholar]
  31. Chen H, Qin J, Wei P, Zhang J, Li Q. 31.  et al. 2009. Effects of leukotriene B4 and prostaglandin E2 on the differentiation of murine Foxp3+ T regulatory cells and Th17 cells. Prostaglandins Leukot. Essent. Fatty Acids 80:195–200 [Google Scholar]
  32. Lee W, Su Kim H, Lee GR. 32.  2015. Leukotrienes induce the migration of Th17 cells. Immunol. Cell Biol. 93:472–29 [Google Scholar]
  33. Baluk P, Fuxe J, Hashizume H, Romano T, Lashnits E. 33.  et al. 2007. Functionally specialized junctions between endothelial cells of lymphatic vessels. J. Exp. Med. 204:2349–62 [Google Scholar]
  34. Stacker SA, Williams SP, Karnezis T, Shayan R, Fox SB, Achen MG. 34.  2014. Lymphangiogenesis and lymphatic vessel remodelling in cancer. Nat. Rev. Cancer 14:159–72 [Google Scholar]
  35. Yao LC, McDonald DM. 35.  2014. Plasticity of airway lymphatics in development and disease. Adv. Anat. Embryol. Cell Biol. 214:41–54 [Google Scholar]
  36. Miteva DO, Rutkowski JM, Dixon JB, Kilarski W, Shields JD, Swartz MA. 36.  2010. Transmural flow modulates cell and fluid transport functions of lymphatic endothelium. Circ. Res. 106:920–31 [Google Scholar]
  37. Makinen T, Norrmen C, Petrova TV. 37.  2007. Molecular mechanisms of lymphatic vascular development. Cell. Mol. Life Sci. 64:1915–29 [Google Scholar]
  38. Kerjaschki D.38.  2014. The lymphatic vasculature revisited. J. Clin. Investig. 124:874–77 [Google Scholar]
  39. Choi I, Lee S, Hong YK. 39.  2012. The new era of the lymphatic system: no longer secondary to the blood vascular system. Cold Spring Harb. Perspect. Med. 2:a006445 [Google Scholar]
  40. Aspelund A, Robciuc MR, Karaman S, Makinen T, Alitalo K. 40.  2016. Lymphatic system in cardiovascular medicine. Circ. Res. 118:515–30 [Google Scholar]
  41. Kaipainen A, Korhonen J, Mustonen T, van Hinsbergh VW, Fang GH. 41.  et al. 1995. Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. PNAS 92:3566–70 [Google Scholar]
  42. Wigle JT, Oliver G. 42.  1999. Prox1 function is required for the development of the murine lymphatic system. Cell 98:769–78 [Google Scholar]
  43. Dumont DJ, Jussila L, Taipale J, Lymboussaki A, Mustonen T. 43.  et al. 1998. Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 282:946–49 [Google Scholar]
  44. Karkkainen MJ, Haiko P, Sainio K, Partanen J, Taipale J. 44.  et al. 2004. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat. Immunol. 5:74–80 [Google Scholar]
  45. Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M. 45.  et al. 1997. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 276:1423–25 [Google Scholar]
  46. Wigle JT, Harvey N, Detmar M, Lagutina I, Grosveld G. 46.  et al. 2002. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J 21:1505–13 [Google Scholar]
  47. Hong YK, Foreman K, Shin JW, Hirakawa S, Curry CL. 47.  et al. 2004. Lymphatic reprogramming of blood vascular endothelium by Kaposi sarcoma-associated herpesvirus. Nat. Genet. 36:683–85 [Google Scholar]
  48. Johnson NC, Dillard ME, Baluk P, McDonald DM, Harvey NL. 48.  et al. 2008. Lymphatic endothelial cell identity is reversible and its maintenance requires Prox1 activity. Genes Dev 22:3282–91 [Google Scholar]
  49. Murtomaki A, Uh MK, Choi YK, Kitajewski C, Borisenko V. 49  et al. 2013. Notch1 functions as a negative regulator of lymphatic endothelial cell differentiation in the venous endothelium. Development 140:2365–76 [Google Scholar]
  50. Hägerling R, Pollmann C, Andreas M, Schmidt C, Nurmi H. 50.  et al. 2013. A novel multistep mechanism for initial lymphangiogenesis in mouse embryos based on ultramicroscopy. EMBO J 32:629–44 [Google Scholar]
  51. Bos FL, Caunt M, Peterson-Maduro J, Planas-Paz L, Kowalski J. 51.  et al. 2011. CCBE1 is essential for mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo. Circ. Res. 109:486–91 [Google Scholar]
  52. Jeltsch M, Jha SK, Tvorogov D, Anisimov A, Leppanen VM. 52.  et al. 2014. CCBE1 enhances lymphangiogenesis via A disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation. Circulation 129:1962–71 [Google Scholar]
  53. Le Guen L, Karpanen T, Schulte D, Harris NC, Koltowska K. 53.  et al. 2014. Ccbe1 regulates Vegfc-mediated induction of Vegfr3 signaling during embryonic lymphangiogenesis. Development 141:1239–49 [Google Scholar]
  54. Yuan L, Moyon D, Pardanaud L, Breant C, Karkkainen MJ. 54.  et al. 2002. Abnormal lymphatic vessel development in neuropilin 2 mutant mice. Development 129:4797–806 [Google Scholar]
  55. Zheng W, Tammela T, Yamamoto M, Anisimov A, Holopainen T. 55.  et al. 2011. Notch restricts lymphatic vessel sprouting induced by vascular endothelial growth factor. Blood 118:1154–62 [Google Scholar]
  56. Yao LC, Baluk P, Srinivasan RS, Oliver G, McDonald DM. 56.  2012. Plasticity of button-like junctions in the endothelium of airway lymphatics in development and inflammation. Am. J. Pathol. 180:2561–75 [Google Scholar]
  57. Yang Y, Oliver G. 57.  2014. Transcriptional control of lymphatic endothelial cell type specification. Adv. Anat. Embryol. Cell Biol. 214:5–22 [Google Scholar]
  58. Petrova TV, Karpanen T, Norrmen C, Mellor R, Tamakoshi T. 58.  et al. 2004. Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Nat. Med. 10:974–81 [Google Scholar]
  59. Norrmén C, Ivanov KI, Cheng J, Zangger N, Delorenzi M. 59.  et al. 2009. FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1. J. Cell Biol. 185:439–57 [Google Scholar]
  60. Sabine A, Agalarov Y, Maby-El Hajjami H, Jaquet M, Hägerling R. 60.  et al. 2012. Mechanotransduction, PROX1, and FOXC2 cooperate to control connexin37 and calcineurin during lymphatic-valve formation. Dev. Cell 22:430–45 [Google Scholar]
  61. Sabine A, Bovay E, Demir CS, Kimura W, Jaquet M. 61.  et al. 2015. FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature. J. Clin. Investig. 125:3861–77 [Google Scholar]
  62. Sweet DT, Jiménez JM, Chang J, Hess PR, Mericko-Ishizuka P. 62.  et al. 2015. Lymph flow regulates collecting lymphatic vessel maturation in vivo. J. Clin. Investig. 125:2995–3007 [Google Scholar]
  63. Levick JR, Michel CC. 63.  2010. Microvascular fluid exchange and the revised Starling principle. Cardiovasc. Res. 87:198–210 [Google Scholar]
  64. Mortimer PS, Rockson SG. 64.  2014. New developments in clinical aspects of lymphatic disease. J. Clin. Investig. 124:915–21 [Google Scholar]
  65. Lim HY, Thiam CH, Yeo KP, Bisoendial R, Hii CS. 65.  et al. 2013. Lymphatic vessels are essential for the removal of cholesterol from peripheral tissues by SR-BI-mediated transport of HDL. Cell Metab 17:671–84 [Google Scholar]
  66. Tammela T, Alitalo K. 66.  2010. Lymphangiogenesis: molecular mechanisms and future promise. Cell 140:460–76 [Google Scholar]
  67. Choe K, Jang JY, Park I, Kim Y, Ahn S. 67.  et al. 2015. Intravital imaging of intestinal lacteals unveils lipid drainage through contractility. J. Clin. Investig. 125:4042–52 [Google Scholar]
  68. Bernier-Latmani J, Cisarovsky C, Demir CS, Bruand M, Jaquet M. 68.  et al. 2015. DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport. J. Clin. Investig. 125:4572–86 [Google Scholar]
  69. Nurmi H, Saharinen P, Zarkada G, Zheng W, Robciuc MR, Alitalo K. 69.  2015. VEGF-C is required for intestinal lymphatic vessel maintenance and lipid absorption. EMBO Mol. Med. 7:1418–25 [Google Scholar]
  70. Randolph GJ, Ivanov S, Zinselmeyer BH, Scallan JP. 70.  2016. The lymphatic system: integral roles in immunity. Annu. Rev. Immunol. 35:31–52 [Google Scholar]
  71. Lämmermann T, Bader BL, Monkley SJ, Worbs T, Wedlich-Söldner R. 71.  et al. 2008. Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature 453:51–55 [Google Scholar]
  72. Overstreet MG, Gaylo A, Angermann BR, Hughson A, Hyun YM. 72.  et al. 2013. Inflammation-induced interstitial migration of effector CD4+ T cells is dependent on integrin αV. Nat. Immunol. 14:949–58 [Google Scholar]
  73. Ma J, Wang JH, Guo YJ, Sy MS, Bigby M. 73.  1994. In vivo treatment with anti-ICAM-1 and anti-LFA-1 antibodies inhibits contact sensitization-induced migration of epidermal Langerhans cells to regional lymph nodes. Cell Immunol 158:389–99 [Google Scholar]
  74. Johnson LA, Clasper S, Holt AP, Lalor PF, Baban D, Jackson DG. 74.  2006. An inflammation-induced mechanism for leukocyte transmigration across lymphatic vessel endothelium. J. Exp. Med. 203:2763–77 [Google Scholar]
  75. Pflicke H, Sixt M. 75.  2009. Preformed portals facilitate dendritic cell entry into afferent lymphatic vessels. J. Exp. Med. 206:2925–35 [Google Scholar]
  76. Förster R, Davalos-Misslitz AC, Rot A. 76.  2008. CCR7 and its ligands: balancing immunity and tolerance. Nat. Rev. Immunol. 8:362–71 [Google Scholar]
  77. Takamatsu H, Takegahara N, Nakagawa Y, Tomura M, Taniguchi M. 77.  et al. 2010. Semaphorins guide the entry of dendritic cells into the lymphatics by activating myosin II. Nat. Immunol. 11:594–600 [Google Scholar]
  78. Gale NW, Prevo R, Espinosa J, Ferguson DJ, Dominguez MG. 78.  et al. 2007. Normal lymphatic development and function in mice deficient for the lymphatic hyaluronan receptor LYVE-1. Mol. Cell. Biol. 27:595–604 [Google Scholar]
  79. Lynskey NN, Banerji S, Johnson LA, Holder KA, Reglinski M. 79.  et al. 2015. Rapid lymphatic dissemination of encapsulated group A streptococci via lymphatic vessel endothelial receptor-1 interaction. PLOS Pathog 11:e1005137 [Google Scholar]
  80. Weber M, Blair E, Simpson CV, O'Hara M, Blackburn PE. 80.  et al. 2004. The chemokine receptor D6 constitutively traffics to and from the cell surface to internalize and degrade chemokines. Mol. Biol. Cell 15:2492–508 [Google Scholar]
  81. Hernandez J, Aung S, Redmond WL, Sherman LA. 81.  2001. Phenotypic and functional analysis of CD8+ T cells undergoing peripheral deletion in response to cross-presentation of self-antigen. J. Exp. Med. 194:707–17 [Google Scholar]
  82. Cohen JN, Guidi CJ, Tewalt EF, Qiao H, Rouhani SJ. 82.  et al. 2010. Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. J. Exp. Med. 207:681–88 [Google Scholar]
  83. Hirosue S, Vokali E, Raghavan VR, Rincon-Restrepo M, Lund AW. 83.  et al. 2014. Steady-state antigen scavenging, cross-presentation, and CD8+ T cell priming: a new role for lymphatic endothelial cells. J. Immunol. 192:5002–11 [Google Scholar]
  84. Rouhani SJ, Eccles JD, Tewalt EF, Engelhard VH. 84.  2014. Regulation of T-cell tolerance by lymphatic endothelial cells. J. Clin. Cell. Immunol. 5:1000242 [Google Scholar]
  85. Dubrot J, Duraes FV, Potin L, Capotosti F, Brighouse D. 85.  et al. 2014. Lymph node stromal cells acquire peptide–MHCII complexes from dendritic cells and induce antigen-specific CD4+ T cell tolerance. J. Exp. Med. 211:1153–66 [Google Scholar]
  86. Swartz MA, Lund AW. 86.  2012. Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity. Nat. Rev. Cancer 12:210–19 [Google Scholar]
  87. Kim H, Kataru RP, Koh GY. 87.  2014. Inflammation-associated lymphangiogenesis: a double-edged sword?. J. Clin. Investig. 124:936–42 [Google Scholar]
  88. Karaman S, Hollmén M, Robciuc MR, Alitalo A, Nurmi H. 88.  et al. 2015. Blockade of VEGF-C and VEGF-D modulates adipose tissue inflammation and improves metabolic parameters under high-fat diet. Mol. Metab. 4:93–105 [Google Scholar]
  89. Karkkainen MJ, Ferrell RE, Lawrence EC, Kimak MA, Levinson KL. 89.  et al. 2000. Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. Nat. Genet. 25:153–59 [Google Scholar]
  90. Gordon K, Schulte D, Brice G, Simpson MA, Roukens MG. 90.  et al. 2013. Mutation in vascular endothelial growth factor-C, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant Milroy-like primary lymphedema. Circ. Res. 112:956–60 [Google Scholar]
  91. Irrthum A, Devriendt K, Chitayat D, Matthijs G, Glade C. 91.  et al. 2003. Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia. Am. J. Hum. Genet. 72:1470–78 [Google Scholar]
  92. Ostergaard P, Simpson MA, Connell FC, Steward CG, Brice G. 92.  et al. 2011. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat. Genet. 43:929–31 [Google Scholar]
  93. Babu S, Nutman TB. 93.  2012. Immunopathogenesis of lymphatic filarial disease. Semin. Immunopathol. 34:847–61 [Google Scholar]
  94. Cormier JN, Askew RL, Mungovan KS, Xing Y, Ross MI, Armer JM. 94.  2010. Lymphedema beyond breast cancer: a systematic review and meta-analysis of cancer-related secondary lymphedema. Cancer 116:5138–49 [Google Scholar]
  95. Avraham T, Yan A, Zampell JC, Daluvoy SV, Haimovitz-Friedman A. 95.  et al. 2010. Radiation therapy causes loss of dermal lymphatic vessels and interferes with lymphatic function by TGF-β1-mediated tissue fibrosis. Am. J. Physiol. Cell Physiol. 299:C589–605 [Google Scholar]
  96. Gould N, Kamelle S, Tillmanns T, Scribner D, Gold M. 96.  et al. 2001. Predictors of complications after inguinal lymphadenectomy. Gynecol. Oncol. 82:329–32 [Google Scholar]
  97. Vignes S, Arrault M, Dupuy A. 97.  2007. Factors associated with increased breast cancer-related lymphedema volume. Acta Oncol 46:1138–42 [Google Scholar]
  98. Treves N.98.  1957. An evaluation of the etiological factors of lymphedema following radical mastectomy. An analysis of 1,007 cases. Cancer 10:444–59 [Google Scholar]
  99. Weitman ES, Aschen SZ, Farias-Eisner G, Albano N, Cuzzone DA. 99.  et al. 2013. Obesity impairs lymphatic fluid transport and dendritic cell migration to lymph nodes. PLOS ONE 8:e70703 [Google Scholar]
  100. Blum KS, Karaman S, Proulx ST, Ochsenbein AM, Luciani P. 100.  et al. 2014. Chronic high-fat diet impairs collecting lymphatic vessel function in mice. PLOS ONE 9:e94713 [Google Scholar]
  101. Greene AK, Grant FD, Slavin SA. 101.  2012. Lower-extremity lymphedema and elevated body-mass index. N. Engl. J. Med. 366:2136–37 [Google Scholar]
  102. Finegold DN, Schacht V, Kimak MA, Lawrence EC, Foeldi E. 102.  et al. 2008. HGF and MET mutations in primary and secondary lymphedema. Lymphat. Res. Biol. 6:65–68 [Google Scholar]
  103. Newman B, Lose F, Kedda MA, Francois M, Ferguson K. 103.  et al. 2012. Possible genetic predisposition to lymphedema after breast cancer. Lymphat. Res. Biol. 10:2–13 [Google Scholar]
  104. Nutman TB.104.  2013. Insights into the pathogenesis of disease in human lymphatic filariasis. Lymphat. Res. Biol. 11:144–48 [Google Scholar]
  105. Bennuru S, Nutman TB. 105.  2009. Lymphangiogenesis and lymphatic remodeling induced by filarial parasites: implications for pathogenesis. PLOS Pathog 5:e1000688 [Google Scholar]
  106. Rao UR, Vickery AC, Kwa BH, Nayar JK. 106.  1996. Regulatory cytokines in the lymphatic pathology of athymic mice infected with Brugia malayi. . Int. J. Parasitol. 26:561–65 [Google Scholar]
  107. Babu S, Nutman TB. 107.  2014. Immunology of lymphatic filariasis. Parasite Immunol 36:338–46 [Google Scholar]
  108. Nelson FK, Greiner DL, Shultz LD, Rajan TV. 108.  1991. The immunodeficient scid mouse as a model for human lymphatic filariasis. J. Exp. Med. 173:659–63 [Google Scholar]
  109. Lal RB, Kumaraswami V, Krishnan N, Nutman TB, Ottesen EA. 109.  1989. Lymphocyte subpopulations in Bancroftian filariasis: activated (DR+) CD8+ T cells in patients with chronic lymphatic obstruction. Clin. Exp. Immunol. 77:77–82 [Google Scholar]
  110. Freedman DO, Horn TD, Maia e Silva CM, Braga C, Maciel A. 110.  1995. Predominant CD8+ infiltrate in limb biopsies of individuals with filarial lymphedema and elephantiasis. Am. J. Trop. Med. Hyg. 53:633–38 [Google Scholar]
  111. Freedman DO, Plier DA, de Almeida A, Miranda J, Braga C. 111.  et al. 1999. Biased TCR repertoire in infiltrating lesional T cells in human Bancroftian filariasis. J. Immunol. 162:1756–64 [Google Scholar]
  112. Babu S, Bhat SQ, Pavan Kumar N, Lipira AB, Kumar S. 112.  et al. 2009. Filarial lymphedema is characterized by antigen-specific Th1 and Th17 proinflammatory responses and a lack of regulatory T cells. PLOS Negl. Trop. Dis. 3:e420 [Google Scholar]
  113. Pathak M, Sharma P, Sharma A, Verma M, Srivastava M, Misra-Bhattacharya S. 113.  2016. Regulatory T-cell neutralization in mice during filariasis helps in parasite clearance by enhancing T helper type 17-mediated pro-inflammatory response. Immunology 147:190–203 [Google Scholar]
  114. Anuradha R, George PJ, Hanna LE, Chandrasekaran V, Kumaran PP. 114.  et al. 2014. Parasite-antigen driven expansion of IL-5− and IL-5+ Th2 human subpopulations in lymphatic filariasis and their differential dependence on IL-10 and TGFβ. PLOS Negl. Trop. Dis. 8:e2658 [Google Scholar]
  115. Anuradha R, George PJ, Hanna LE, Chandrasekaran V, Kumaran P. 115.  et al. 2013. IL-4-, TGF-β-, and IL-1-dependent expansion of parasite antigen-specific Th9 cells is associated with clinical pathology in human lymphatic filariasis. J. Immunol. 191:2466–73 [Google Scholar]
  116. Olszewski WL, Jamal S, Manokaran G, Lukomska B, Kubicka U. 116.  1993. Skin changes in filarial and non-filarial lymphoedema of the lower extremities. Trop. Med. Parasitol. 44:40–44 [Google Scholar]
  117. Zampell JC, Yan A, Elhadad S, Avraham T, Weitman E, Mehrara BJ. 117.  2012. CD4+ cells regulate fibrosis and lymphangiogenesis in response to lymphatic fluid stasis. PLOS ONE 7:e49940 [Google Scholar]
  118. Avraham T, Daluvoy S, Zampell J, Yan A, Haviv YS. 118.  et al. 2010. Blockade of transforming growth factor-β1 accelerates lymphatic regeneration during wound repair. Am. J. Pathol. 177:3202–14 [Google Scholar]
  119. Avraham T, Zampell JC, Yan A, Elhadad S, Weitman ES. 119.  et al. 2013. Th2 differentiation is necessary for soft tissue fibrosis and lymphatic dysfunction resulting from lymphedema. FASEB J 27:1114–26 [Google Scholar]
  120. Savetsky IL, Ghanta S, Gardenier JC, Torrisi JS, Garcia Nores GD. 120.  et al. 2015. Th2 cytokines inhibit lymphangiogenesis. PLOS ONE 10:e0126908 [Google Scholar]
  121. Shin K, Kataru RP, Park HJ, Kwon BI, Kim TW. 121.  et al. 2015. TH2 cells and their cytokines regulate formation and function of lymphatic vessels. Nat. Commun. 6:6196 [Google Scholar]
  122. Gousopoulos E, Proulx ST, Bachmann SB, Scholl J, Dionyssiou D. 122.  et al. 2016. Regulatory T cell transfer ameliorates lymphedema and promotes lymphatic vessel function. JCI Insight 1:e89081 [Google Scholar]
  123. Ogata F, Fujiu K, Matsumoto S, Nakayama Y, Shibata M. 123.  et al. 2016. Excess lymphangiogenesis cooperatively induced by macrophages and CD4+ T cells drives the pathogenesis of lymphedema. J. Investig. Dermatol. 136:706–14 [Google Scholar]
  124. Vannella KM, Wynn TA. 124.  2017. Mechanisms of organ injury and repair by macrophages. Annu. Rev. Physiol. 79:593–617 [Google Scholar]
  125. Sica A, Erreni M, Allavena P, Porta C. 125.  2015. Macrophage polarization in pathology. Cell. Mol. Life Sci. 72:4111–26 [Google Scholar]
  126. Ghanta S, Cuzzone DA, Torrisi JS, Albano NJ, Joseph WJ. 126.  et al. 2015. Regulation of inflammation and fibrosis by macrophages in lymphedema. Am. J. Physiol. Heart Circ. Physiol. 308:H1065–77 [Google Scholar]
  127. Rutkowski JM, Moya M, Johannes J, Goldman J, Swartz MA. 127.  2006. Secondary lymphedema in the mouse tail: lymphatic hyperplasia, VEGF-C upregulation, and the protective role of MMP-9. Microvasc. Res. 72:161–71 [Google Scholar]
  128. Zampell JC, Elhadad S, Avraham T, Weitman E, Aschen S. 128.  et al. 2012. Toll-like receptor deficiency worsens inflammation and lymphedema after lymphatic injury. Am. J. Physiol. Cell Physiol. 302:C709–19 [Google Scholar]
  129. Tabibiazar R, Cheung L, Han J, Swanson J, Beilhack A. 129.  et al. 2006. Inflammatory manifestations of experimental lymphatic insufficiency. PLOS Med 3:e254 [Google Scholar]
  130. Nakamura K, Radhakrishnan K, Wong YM, Rockson SG. 130.  2009. Anti-inflammatory pharmacotherapy with ketoprofen ameliorates experimental lymphatic vascular insufficiency in mice. PLOS ONE 4:e8380 [Google Scholar]
  131. Baluk P, Yao LC, Feng J, Romano T, Jung SS. 131.  et al. 2009. TNF-α drives remodeling of blood vessels and lymphatics in sustained airway inflammation in mice. J. Clin. Investig. 119:2954–64 [Google Scholar]
  132. Ambrus JL Jr., Haneiwich S, Chesky L, McFarland P, Engler RJ.132.  1991. Improved in vitro antigen-specific antibody synthesis in two patients with common variable immunodeficiency taking an oral cyclooxygenase and lipoxygenase inhibitor (ketoprofen). J. Allergy Clin. Immunol. 88:775–83 [Google Scholar]
  133. Tian W, Rockson SG, Jiang X, Kim J, Begaye A. 133.  et al. 2017. Leukotriene B4 antagonism ameliorates experimental lymphedema. Sci. Transl. Med 9:eaal3920 [Google Scholar]
  134. Murtomaki A, Uh MK, Kitajewski C, Zhao J, Nagasaki T. 134.  et al. 2014. Notch signaling functions in lymphatic valve formation. Development 141:2446–51 [Google Scholar]
  135. Tager AM, Bromley SK, Medoff BD, Islam SA, Bercury SD. 135.  et al. 2003. Leukotriene B4 receptor BLT1 mediates early effector T cell recruitment. Nat. Immunol. 4:982–90 [Google Scholar]
  136. Ott VL, Cambier JC, Kappler J, Marrack P, Swanson BJ. 136.  2003. Mast cell-dependent migration of effector CD8+ T cells through production of leukotriene B4. Nat. Immunol. 4:974–81 [Google Scholar]
  137. Wynn TA.137.  2004. Fibrotic disease and the TH1/TH2 paradigm. Nat. Rev. Immunol. 4:583–94 [Google Scholar]
  138. Cho S, Roh K, Park J, Park YS, Lee M. 138.  et al. 2017. Hydrolysis of hyaluronic acid in lymphedematous tissue alleviates fibrogenesis via TH1 cell-mediated cytokine expression. Sci. Rep. 7:35 [Google Scholar]
  139. Lv J, Xiong Y, Li W, Yang W, Zhao L, He R. 139.  2017. BLT1 mediates bleomycin-induced lung fibrosis independently of neutrophils and CD4+ T cells. J. Immunol. 198:1673–84 [Google Scholar]
  140. Qian J, Tian W, Jiang X, Tamosiuniene R, Sung YK. 140.  et al. 2015. Leukotriene B4 activates pulmonary artery adventitial fibroblasts in pulmonary hypertension. Hypertension 66:1227–39 [Google Scholar]
  141. Lynch LL, Mendez U, Waller AB, Gillette AA, Guillory RJ 2nd, Goldman J. 141.  2015. Fibrosis worsens chronic lymphedema in rodent tissues. Am. J. Physiol. Heart Circ. Physiol. 308:H1229–36 [Google Scholar]
  142. Aschen S, Zampell JC, Elhadad S, Weitman E, De Brot M, Mehrara BJ. 142.  2012. Regulation of adipogenesis by lymphatic fluid stasis part II: expression of adipose differentiation genes. Plast. Reconstr. Surg. 129:838–47 [Google Scholar]
  143. Zampell JC, Aschen S, Weitman ES, Yan A, Elhadad S. 143.  et al. 2012. Regulation of adipogenesis by lymphatic fluid stasis part I: adipogenesis, fibrosis, and inflammation. Plast. Reconstr. Surg. 129:825–34 [Google Scholar]
  144. Cuzzone DA, Weitman ES, Albano NJ, Ghanta S, Savetsky IL. 144.  et al. 2014. IL-6 regulates adipose deposition and homeostasis in lymphedema. Am. J. Physiol. Heart Circ. Physiol. 306:H1426–34 [Google Scholar]
/content/journals/10.1146/annurev-physiol-022516-034008
Loading
Lymphatic Dysfunction, Leukotrienes, and Lymphedema
Annual Review of Physiology 80, 49 (2018); https://doi.org/10.1146/annurev-physiol-022516-034008
/content/journals/10.1146/annurev-physiol-022516-034008
/content/journals/10.1146/annurev-physiol-022516-034008
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error