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Annual Review of Physiology

Volume 87, 2025

The Lymphatic Vasculature in Lung Homeostasis and Disease

  • Katharina Maisel1 and Hasina Outtz Reed2
  • 1Fischell Department of Bioengineering, University of Maryland, College Park, Maryland, USA 2Department of Medicine and Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA; email: [email protected]
  • Vol. 87:421-446 (Volume publication date February 2025)
  • First published as a Review in Advance on November 12, 2024
  • Copyright © 2025 by the author(s).
    This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See credit lines of images or other third-party material in this article for license information.

Abstract

The lymphatic vasculature maintains lung homeostasis via fluid drainage in the form of lymph and by facilitating immune surveillance and leukocyte trafficking to the draining lymph nodes. Previous studies in both humans and animal models have demonstrated an important role for lymphatics in lung function from the neonatal period through adulthood. In addition, changes in the lymphatic vasculature have been observed in many respiratory diseases, and there is emerging evidence of a causative role for lymphatic dysfunction in the initiation and progression of lung pathology. Despite advances in the field, there are still many unanswered questions, and a more comprehensive understanding of the mechanisms by which the lymphatics affect lung homeostasis and the response to lung injury is needed. In this review, we discuss our current knowledge of the structure, function, and role of the lymphatics in the lung and how these vessels are involved in respiratory disease.

Keyword(s): lung disease, lung injury, lymphatics, pulmonary function
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2025-02-10
2025-06-15
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Literature Cited

  1. 1.
    Natale G, Bocci G, Ribatti D. 2017.. Scholars and scientists in the history of the lymphatic system. . J. Anat. 231::417–29
     [Crossref] [Google Scholar]
  2. 2.
    Chikly B. 1997.. Who discovered the lymphatic system?. Lymphology 30::186–93
     [Google Scholar]
  3. 3.
    Trapnell DH. 1965.. Man's understanding of the lymphatics, with particular reference to the lung. . Proc. R. Soc. Med. 58::37–40
     [Google Scholar]
  4. 4.
    Cruikshank WC. 1786.. The Anatomy of the Absorbing Vessels of the Human Body. London:: G. Nicol
     [Google Scholar]
  5. 5.
    Miller WS. 1937.. The Lung. Springfield, IL:: Charles C. Thomas
     [Google Scholar]
  6. 6.
    Hong YK, Shin JW, Detmar M. 2004.. Development of the lymphatic vascular system: a mystery unravels. . Dev. Dyn. 231::462–73
     [Crossref] [Google Scholar]
  7. 7.
    Xu W, Harris NR, Caron KM. 2021.. Lymphatic vasculature: an emerging therapeutic target and drug delivery route. . Annu. Rev. Med. 72::167–82
     [Crossref] [Google Scholar]
  8. 8.
    Oliver G, Kipnis J, Randolph GJ, Harvey NL. 2020.. The lymphatic vasculature in the 21st century: novel functional roles in homeostasis and disease. . Cell 182::270–96
     [Crossref] [Google Scholar]
  9. 9.
    Stump B, Cui Y, Kidambi P, Lamattina AM, El-Chemaly S. 2017.. Lymphatic changes in respiratory diseases: more than just remodeling of the lung?. Am. J. Respir. Cell Mol. Biol. 57::272–79
     [Crossref] [Google Scholar]
  10. 10.
    El-Chemaly S, Levine SJ, Moss J. 2008.. Lymphatics in lung disease. . Ann. N. Y. Acad. Sci. 1131::195–202
     [Crossref] [Google Scholar]
  11. 11.
    Summers BD, Kim K, Clement CC, Khan Z, Thangaswamy S, et al. 2022.. Lung lymphatic thrombosis and dysfunction caused by cigarette smoke exposure precedes emphysema in mice. . Sci. Rep. 12::5012
     [Crossref] [Google Scholar]
  12. 12.
    Reed HO, Wang L, Sonett J, Chen M, Yang J, et al. 2019.. Lymphatic impairment leads to pulmonary tertiary lymphoid organ formation and alveolar damage. . J. Clin. Investig. 129::2514–26
     [Crossref] [Google Scholar]
  13. 13.
    Mori M, Andersson CK, Graham GJ, Löfdahl CG, Erjefält JS. 2013.. Increased number and altered phenotype of lymphatic vessels in peripheral lung compartments of patients with COPD. . Respir. Res. 14::65
     [Crossref] [Google Scholar]
  14. 14.
    Jakus Z, Gleghorn JP, Enis DR, Sen A, Chia S, et al. 2014.. Lymphatic function is required prenatally for lung inflation at birth. . J. Exp. Med. 211::815–26
     [Crossref] [Google Scholar]
  15. 15.
    Ranvier L. 1895.. Étude morphologique des capillaires lymphatiques des mammifères. . Comptes Rendus 121::856–58
     [Google Scholar]
  16. 16.
    Sabin FR. 1902.. On the origin of the lymphatic system from the veins and the development of the lymph hearts and thoracic duct in the pig. . Am. J. Anat. 1::367–89
     [Crossref] [Google Scholar]
  17. 17.
    Srinivasan RS, Dillard ME, Lagutin OV, Lin FJ, Tsai S, et al. 2007.. Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature. . Genes Dev. 21::2422–32
     [Crossref] [Google Scholar]
  18. 18.
    Wigle JT, Oliver G. 1999.. Prox1 function is required for the development of the murine lymphatic system. . Cell 98::769–78
     [Crossref] [Google Scholar]
  19. 19.
    Oliver G. 2004.. Lymphatic vasculature development. . Nat. Rev. Immunol. 4::35–45
     [Crossref] [Google Scholar]
  20. 20.
    Srinivasan RS, Escobedo N, Yang Y, Interiano A, Dillard ME, et al. 2014.. The Prox1–Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors. . Genes Dev. 28::2175–87
     [Crossref] [Google Scholar]
  21. 21.
    Hong YK, Harvey N, Noh YH, Schacht V, Hirakawa S, et al. 2002.. Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate. . Dev. Dyn. 225::351–57
     [Crossref] [Google Scholar]
  22. 22.
    Petrova TV, Makinen T, Makela TP, Saarela J, Virtanen I, et al. 2002.. Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. . EMBO J. 21::4593–99
     [Crossref] [Google Scholar]
  23. 23.
    Hess PR, Rawnsley DR, Jakus Z, Yang Y, Sweet DT, et al. 2014.. Platelets mediate lymphovenous hemostasis to maintain blood-lymphatic separation throughout life. . J. Clin. Investig. 124::273–84
     [Crossref] [Google Scholar]
  24. 24.
    Bertozzi CC, Schmaier AA, Mericko P, Hess PR, Zou Z, et al. 2010.. Platelets regulate lymphatic vascular development through CLEC-2–SLP-76 signaling. . Blood 116::661–70
     [Crossref] [Google Scholar]
  25. 25.
    Kulkarni RM, Herman A, Ikegami M, Greenberg JM, Akeson AL. 2011.. Lymphatic ontogeny and effect of hypoplasia in developing lung. . Mech. Dev. 128::29–40
     [Crossref] [Google Scholar]
  26. 26.
    van der Putte SC. 1975.. The early development of the lymphatic system in mouse embryos. . Acta Morphol. Neerl. Scand. 13::245–86
     [Google Scholar]
  27. 27.
    Yang Y, Garcia-Verdugo JM, Soriano-Navarro M, Srinivasan RS, Scallan JP, et al. 2012.. Lymphatic endothelial progenitors bud from the cardinal vein and intersomitic vessels in mammalian embryos. . Blood 120::2340–48
     [Crossref] [Google Scholar]
  28. 28.
    Yaniv K, Isogai S, Castranova D, Dye L, Hitomi J, Weinstein BM. 2006.. Live imaging of lymphatic development in the zebrafish. . Nat. Med. 12::711–16
     [Crossref] [Google Scholar]
  29. 29.
    Huntington GS, McClure CFW. 1910.. The anatomy and development of the jugular lymph sacs in the domestic cat (Felis domestica). . Am. J. Anat. 10::177–312
     [Crossref] [Google Scholar]
  30. 30.
    Buttler K, Kreysing A, von Kaisenberg CS, Schweigerer L, Gale N, et al. 2006.. Mesenchymal cells with leukocyte and lymphendothelial characteristics in murine embryos. . Dev. Dyn. 235::1554–62
     [Crossref] [Google Scholar]
  31. 31.
    Martinez-Corral I, Ulvmar MH, Stanczuk L, Tatin F, Kizhatil K, et al. 2015.. Nonvenous origin of dermal lymphatic vasculature. . Circ. Res. 116::1649–54
     [Crossref] [Google Scholar]
  32. 32.
    Klotz L, Norman S, Vieira JM, Masters M, Rohling M, et al. 2015.. Cardiac lymphatics are heterogeneous in origin and respond to injury. . Nature 522::62–67
     [Crossref] [Google Scholar]
  33. 33.
    Mahadevan A, Welsh IC, Sivakumar A, Gludish DW, Shilvock AR, et al. 2014.. The left-right Pitx2 pathway drives organ-specific arterial and lymphatic development in the intestine. . Dev. Cell 31::690–706
     [Crossref] [Google Scholar]
  34. 34.
    Kambouchner M, Bernaudin JF. 2009.. Intralobular pulmonary lymphatic distribution in normal human lung using D2-40 antipodoplanin immunostaining. . J. Histochem. Cytochem. 57::643–48
     [Crossref] [Google Scholar]
  35. 35.
    Lauweryns JM, Baert JH. 1977.. Alveolar clearance and the role of the pulmonary lymphatics. . Am. Rev. Respir. Dis. 115::625–83
     [Google Scholar]
  36. 36.
    Marchetti C, Poggi P, Clement MG, Aguggini G, Piacentini C, Icaro-Cornaglia A. 1994.. Lymphatic capillaries of the pig lung: TEM and SEM observations. . Anat. Rec. 238::368–73
     [Crossref] [Google Scholar]
  37. 37.
    Sozio F, Rossi A, Weber E, Abraham DJ, Nicholson AG, et al. 2012.. Morphometric analysis of intralobular, interlobular and pleural lymphatics in normal human lung. . J. Anat. 220::396–404
     [Crossref] [Google Scholar]
  38. 38.
    Lai-Fook SJ. 2004.. Pleural mechanics and fluid exchange. . Physiol. Rev. 84::385–410
     [Crossref] [Google Scholar]
  39. 39.
    Zocchi L. 2002.. Physiology and pathophysiology of pleural fluid turnover. . Eur. Respir. J. 20::1545–58
     [Crossref] [Google Scholar]
  40. 40.
    Baluk P, McDonald DM. 2018.. Imaging lymphatics in mouse lungs. . Methods Mol. Biol. 1846::161–80
     [Crossref] [Google Scholar]
  41. 41.
    Baluk P, McDonald DM. 2008.. Markers for microscopic imaging of lymphangiogenesis and angiogenesis. . Ann. N. Y. Acad. Sci. 1131::1–12
     [Crossref] [Google Scholar]
  42. 42.
    Choi I, Chung HK, Ramu S, Lee HN, Kim KE, et al. 2011.. Visualization of lymphatic vessels by Prox1-promoter directed GFP reporter in a bacterial artificial chromosome-based transgenic mouse. . Blood 117::362–5
     [Crossref] [Google Scholar]
  43. 43.
    Schupp JC, Adams TS, Cosme C Jr., Raredon MSB, Yuan Y, et al. 2021.. Integrated single-cell atlas of endothelial cells of the human lung. . Circulation 144::286–302
     [Crossref] [Google Scholar]
  44. 44.
    Broaddus VC, Ernst JD, King TE Jr., Lazarus SC, Sarmiento KF, et al., eds. 2021.. Murray & Nadel's Textbook of Respiratory Medicine, Vol. 1. Philadelphia:: Elsevier. , 7th ed..
     [Google Scholar]
  45. 45.
    Egashira R, Tanaka T, Imaizumi T, Senda K, Doki Y, et al. 2013.. Differential distribution of lymphatic clearance between upper and lower regions of the lung. . Respirology 18::348–53
     [Crossref] [Google Scholar]
  46. 46.
    Meinecke AK, Nagy N, Lago GD, Kirmse S, Klose R, et al. 2012.. Aberrant mural cell recruitment to lymphatic vessels and impaired lymphatic drainage in a murine model of pulmonary fibrosis. . Blood 119::5931–42
     [Crossref] [Google Scholar]
  47. 47.
    Mackersie RC, Christensen J, Lewis FR. 1987.. The role of pulmonary lymphatics in the clearance of hydrostatic pulmonary edema. . J. Surg. Res. 43::495–504
     [Crossref] [Google Scholar]
  48. 48.
    Humphreys PW, Normand IC, Reynolds EO, Strang LB. 1967.. Pulmonary lymph flow and the uptake of liquid from the lungs of the lamb at the start of breathing. . J. Physiol. 193::1–29
     [Crossref] [Google Scholar]
  49. 49.
    Staub NC. 1971.. Steady state pulmonary transvascular water filtration in unanesthetized sheep. . Circ. Res. 28:(Suppl. 1):135–39
     [Google Scholar]
  50. 50.
    Pearse DB, Searcy RM, Mitzner W, Permutt S, Sylvester JT. 2005.. Effects of tidal volume and respiratory frequency on lung lymph flow. . J. Appl. Physiol. 99::556–63
     [Crossref] [Google Scholar]
  51. 51.
    Weber E, Sozio F, Borghini A, Sestini P, Renzoni E. 2018.. Pulmonary lymphatic vessel morphology: a review. . Ann. Anat. 218::110–17
     [Crossref] [Google Scholar]
  52. 52.
    Gashev AA. 2002.. Physiologic aspects of lymphatic contractile function: current perspectives. . Ann. N. Y. Acad. Sci. 979::178–87
     [Crossref] [Google Scholar]
  53. 53.
    Mislin H. 1976.. Active contractility of the lymphangion and coordination of lymphangion chains. . Experientia 32::820–22
     [Crossref] [Google Scholar]
  54. 54.
    Zawieja DC. 2009.. Contractile physiology of lymphatics. . Lymphat. Res. Biol. 7::87–96
     [Crossref] [Google Scholar]
  55. 55.
    Baluk P, Fuxe J, Hashizume H, Romano T, Lashnits E, et al. 2007.. Functionally specialized junctions between endothelial cells of lymphatic vessels. . J. Exp. Med. 204::2349–62
     [Crossref] [Google Scholar]
  56. 56.
    Zhang F, Zarkada G, Yi S, Eichmann A. 2020.. Lymphatic endothelial cell junctions: molecular regulation in physiology and diseases. . Front. Physiol. 11::509
     [Crossref] [Google Scholar]
  57. 57.
    Baluk P, McDonald DM. 2022.. Buttons and zippers: endothelial junctions in lymphatic vessels. . Cold Spring Harb. Perspect. Med. 12::a041178
     [Crossref] [Google Scholar]
  58. 58.
    McDonald DM. 2018.. Tighter lymphatic junctions prevent obesity. . Science 361::551–52
     [Crossref] [Google Scholar]
  59. 59.
    Maldonado-Zimbron VE, Hong J, Russell P, Trevaskis NL, Windsor JA, Phillips ARJ. 2021.. Methods for studying pulmonary lymphatics. . Eur. Respir. J. 57::2004106
     [Crossref] [Google Scholar]
  60. 60.
    Ding BS, Nolan DJ, Butler JM, James D, Babazadeh AO, et al. 2010.. Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. . Nature 468::310–15
     [Crossref] [Google Scholar]
  61. 61.
    Rishi AK, Joyce-Brady M, Fisher J, Dobbs LG, Floros J, et al. 1995.. Cloning, characterization, and development expression of a rat lung alveolar type I cell gene in embryonic endodermal and neural derivatives. . Dev. Biol. 167::294–306
     [Crossref] [Google Scholar]
  62. 62.
    Vigl B, Aebischer D, Nitschké M, Iolyeva M, Röthlin T, et al. 2011.. Tissue inflammation modulates gene expression of lymphatic endothelial cells and dendritic cell migration in a stimulus-dependent manner. . Blood 118::205–15
     [Crossref] [Google Scholar]
  63. 63.
    Huggenberger R, Siddiqui SS, Brander D, Ullmann S, Zimmermann K, et al. 2011.. An important role of lymphatic vessel activation in limiting acute inflammation. . Blood 117::4667–78
     [Crossref] [Google Scholar]
  64. 64.
    Kretschmer S, Dethlefsen I, Hagner-Benes S, Marsh LM, Garn H, König P. 2013.. Visualization of intrapulmonary lymph vessels in healthy and inflamed murine lung using CD90/Thy-1 as a marker. . PLOS ONE 8::e55201
     [Crossref] [Google Scholar]
  65. 65.
    Takeda A, Hollmen M, Dermadi D, Pan J, Brulois KF, et al. 2019.. Single-cell survey of human lymphatics unveils marked endothelial cell heterogeneity and mechanisms of homing for neutrophils. . Immunity 51::561–72.e5
     [Crossref] [Google Scholar]
  66. 66.
    Xiang M, Grosso RA, Takeda A, Pan J, Bekkhus T, et al. 2020.. A single-cell transcriptional roadmap of the mouse and human lymph node lymphatic vasculature. . Front. Cardiovasc. Med. 7::52
     [Crossref] [Google Scholar]
  67. 67.
    Fujimoto N, He Y, D'Addio M, Tacconi C, Detmar M, Dieterich LC. 2020.. Single-cell mapping reveals new markers and functions of lymphatic endothelial cells in lymph nodes. . PLOS Biol. 18::e3000704
     [Crossref] [Google Scholar]
  68. 68.
    Arroz-Madeira S, Bekkhus T, Ulvmar MH, Petrova TV. 2023.. Lessons of vascular specialization from secondary lymphoid organ lymphatic endothelial cells. . Circ. Res. 132::1203–25
     [Crossref] [Google Scholar]
  69. 69.
    Sauler M, McDonough JE, Adams TS, Kothapalli N, Barnthaler T, et al. 2022.. Characterization of the COPD alveolar niche using single-cell RNA sequencing. . Nat. Commun. 13::494
     [Crossref] [Google Scholar]
  70. 70.
    Adams TS, Schupp JC, Poli S, Ayaub EA, Neumark N, et al. 2020.. Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis. . Sci. Adv. 6::eaba1983
     [Crossref] [Google Scholar]
  71. 71.
    Bland RD, Hansen TN, Haberkern CM, Bressack MA, Hazinski TA, et al. 1982.. Lung fluid balance in lambs before and after birth. . J. Appl. Physiol. 53::992–1004
     [Crossref] [Google Scholar]
  72. 72.
    Hummler E, Barker P, Gatzy J, Beermann F, Verdumo C, et al. 1996.. Early death due to defective neonatal lung liquid clearance in αENaC-deficient mice. . Nat. Genet. 12::325–28
     [Crossref] [Google Scholar]
  73. 73.
    Miserocchi G, Poskurica BH, Del Fabbro M. 1994.. Pulmonary interstitial pressure in anesthetized paralyzed newborn rabbits. . J. Appl. Physiol. 77::2260–68
     [Crossref] [Google Scholar]
  74. 74.
    Yao LC, Baluk P, Srinivasan RS, Oliver G, McDonald DM. 2012.. Plasticity of button-like junctions in the endothelium of airway lymphatics in development and inflammation. . Am. J. Pathol. 180::2561–75
     [Crossref] [Google Scholar]
  75. 75.
    Fu S, Wang Y, Bin E, Huang H, Wang F, Tang N. 2023.. c-JUN-mediated transcriptional responses in lymphatic endothelial cells are required for lung fluid clearance at birth. . PNAS 120::e2215449120
     [Crossref] [Google Scholar]
  76. 76.
    Pelosi P, Rocco PR, Negrini D, Passi A. 2007.. The extracellular matrix of the lung and its role in edema formation. . An. Acad. Bras. Cienc. 79::285–97
     [Crossref] [Google Scholar]
  77. 77.
    Schraufnagel DE. 2010.. Lung lymphatic anatomy and correlates. . Pathophysiology 17::337–43
     [Crossref] [Google Scholar]
  78. 78.
    Staub NC. 1974.. Pulmonary edema. . Physiol. Rev. 54::678–811
     [Crossref] [Google Scholar]
  79. 79.
    Staub NC, Taylor AE. 1984.. Edema. New York:: Raven
     [Google Scholar]
  80. 80.
    Jahnsen FL, Strickland DH, Thomas JA, Tobagus IT, Napoli S, et al. 2006.. Accelerated antigen sampling and transport by airway mucosal dendritic cells following inhalation of a bacterial stimulus. . J. Immunol. 177::5861–67
     [Crossref] [Google Scholar]
  81. 81.
    Asokananthan N, Graham PT, Stewart DJ, Bakker AJ, Eidne KA, et al. 2002.. House dust mite allergens induce proinflammatory cytokines from respiratory epithelial cells: the cysteine protease allergen, Der p 1, activates protease-activated receptor (PAR)-2 and inactivates PAR-1. . J. Immunol. 169::4572–78
     [Crossref] [Google Scholar]
  82. 82.
    Chieppa M, Rescigno M, Huang AY, Germain RN. 2006.. Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement. . J. Exp. Med. 203::2841–52
     [Crossref] [Google Scholar]
  83. 83.
    Holt PG, Haining S, Nelson DJ, Sedgwick JD. 1994.. Origin and steady-state turnover of class II MHC-bearing dendritic cells in the epithelium of the conducting airways. . J. Immunol. 153::256–61
     [Crossref] [Google Scholar]
  84. 84.
    Liu K, Victora GD, Schwickert TA, Guermonprez P, Meredith MM, et al. 2009.. In vivo analysis of dendritic cell development and homeostasis. . Science 324::392–97
     [Crossref] [Google Scholar]
  85. 85.
    Liu H, Jakubzick C, Osterburg AR, Nelson RL, Gupta N, et al. 2017.. Dendritic cell trafficking and function in rare lung diseases. . Am. J. Respir. Cell Mol. Biol. 57::393–402
     [Crossref] [Google Scholar]
  86. 86.
    Liu K, Waskow C, Liu X, Yao K, Hoh J, Nussenzweig M. 2007.. Origin of dendritic cells in peripheral lymphoid organs of mice. . Nat. Immunol. 8::578–83
     [Crossref] [Google Scholar]
  87. 87.
    Legge KL, Braciale TJ. 2003.. Accelerated migration of respiratory dendritic cells to the regional lymph nodes is limited to the early phase of pulmonary infection. . Immunity 18::265–77
     [Crossref] [Google Scholar]
  88. 88.
    Johnson LA, Jackson DG. 2014.. Control of dendritic cell trafficking in lymphatics by chemokines. . Angiogenesis 17::335–45
     [Crossref] [Google Scholar]
  89. 89.
    Maisel K, Hrusch CL, Medellin JEG, Potin L, Chapel DB, et al. 2021.. Pro-lymphangiogenic VEGFR-3 signaling modulates memory T cell responses in allergic airway inflammation. . Mucosal Immunol. 14::144–51
     [Crossref] [Google Scholar]
  90. 90.
    Russo E, Teijeira A, Vaahtomeri K, Willrodt AH, Bloch JS, et al. 2016.. Intralymphatic CCL21 promotes tissue egress of dendritic cells through afferent lymphatic vessels. . Cell Rep. 14::1723–34
     [Crossref] [Google Scholar]
  91. 91.
    Friess MC, Kritikos I, Schineis P, Medina-Sanchez JD, Gkountidi AO, et al. 2022.. Mechanosensitive ACKR4 scavenges CCR7 chemokines to facilitate T cell de-adhesion and passive transport by flow in inflamed afferent lymphatics. . Cell Rep. 38::110334
     [Crossref] [Google Scholar]
  92. 92.
    Vermaelen K, Pauwels R. 2003.. Accelerated airway dendritic cell maturation, trafficking, and elimination in a mouse model of asthma. . Am. J. Respir. Cell Mol. Biol. 29::405–9
     [Crossref] [Google Scholar]
  93. 93.
    Grayson MH, Ramos MS, Rohlfing MM, Kitchens R, Wang HD, et al. 2007.. Controls for lung dendritic cell maturation and migration during respiratory viral infection. . J. Immunol. 179::1438–48
     [Crossref] [Google Scholar]
  94. 94.
    GeurtsvanKessel CH, Lambrecht BN. 2008.. Division of labor between dendritic cell subsets of the lung. . Mucosal Immunol. 1::442–50
     [Crossref] [Google Scholar]
  95. 95.
    Jakubzick C, Tacke F, Llodra J, van Rooijen N, Randolph GJ. 2006.. Modulation of dendritic cell trafficking to and from the airways. . J. Immunol. 176::3578–84
     [Crossref] [Google Scholar]
  96. 96.
    Ballesteros-Tato A, León B, Lund FE, Randall TD. 2010.. Temporal changes in dendritic cell subsets, cross-priming and costimulation via CD70 control CD8+ T cell responses to influenza. . Nat. Immunol. 11::216–24
     [Crossref] [Google Scholar]
  97. 97.
    Johnson LA, Clasper S, Holt AP, Lalor PF, Baban D, Jackson DG. 2006.. An inflammation-induced mechanism for leukocyte transmigration across lymphatic vessel endothelium. . J. Exp. Med. 203::2763–77
     [Crossref] [Google Scholar]
  98. 98.
    Pham TH, Okada T, Matloubian M, Lo CG, Cyster JG. 2008.. S1P1 receptor signaling overrides retention mediated by Gαi-coupled receptors to promote T cell egress. . Immunity 28::122–33
     [Crossref] [Google Scholar]
  99. 99.
    Mandala S, Hajdu R, Bergstrom J, Quackenbush E, Xie J, et al. 2002.. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. . Science 296::346–49
     [Crossref] [Google Scholar]
  100. 100.
    Yen JH, Khayrullina T, Ganea D. 2008.. PGE2-induced metalloproteinase-9 is essential for dendritic cell migration. . Blood 111::260–70
     [Crossref] [Google Scholar]
  101. 101.
    Baluk P, Tammela T, Ator E, Lyubynska N, Achen MG, et al. 2005.. Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation. . J. Clin. Investig. 115::247–57
     [Crossref] [Google Scholar]
  102. 102.
    Detoraki A, Granata F, Staibano S, Rossi FW, Marone G, Genovese A. 2010.. Angiogenesis and lymphangiogenesis in bronchial asthma. . Allergy 65::946–58
     [Crossref] [Google Scholar]
  103. 103.
    Ebina M. 2008.. Remodeling of airway walls in fatal asthmatics decreases lymphatic distribution; beyond thickening of airway smooth muscle layers. . Allergol. Int. 57::165–74
     [Crossref] [Google Scholar]
  104. 104.
    Moldobaeva A, Jenkins J, Zhong Q, Wagner EM. 2017.. Lymphangiogenesis in rat asthma model. . Angiogenesis 20::73–84
     [Crossref] [Google Scholar]
  105. 105.
    Baluk P, Naikawadi RP, Kim S, Rodriguez F, Choi D, et al. 2020.. Lymphatic proliferation ameliorates pulmonary fibrosis after lung injury. . Am. J. Pathol. 190::2355–75
     [Crossref] [Google Scholar]
  106. 106.
    El-Chemaly S, Malide D, Zudaire E, Ikeda Y, Weinberg BA, et al. 2009.. Abnormal lymphangiogenesis in idiopathic pulmonary fibrosis with insights into cellular and molecular mechanisms. . PNAS 106::3958–63
     [Crossref] [Google Scholar]
  107. 107.
    Yamashita M, Mouri T, Niisato M, Kowada K, Kobayashi H, et al. 2013.. Heterogeneous characteristics of lymphatic microvasculatures associated with pulmonary sarcoid granulomas. . Ann. Am. Thorac. Soc. 10::90–97
     [Crossref] [Google Scholar]
  108. 108.
    Glasgow CG, El-Chemaly S, Moss J. 2012.. Lymphatics in lymphangioleiomyomatosis and idiopathic pulmonary fibrosis. . Eur. Respir. Rev. 21::196–206
     [Crossref] [Google Scholar]
  109. 109.
    Ebina M. 2017.. Pathognomonic remodeling of blood and lymphatic capillaries in idiopathic pulmonary fibrosis. . Respir. Investig. 55::2–9
     [Crossref] [Google Scholar]
  110. 110.
    Zhang PH, Zhang WW, Wang SS, Wu CH, Ding YD, et al. 2024.. Efficient pulmonary lymphatic drainage is necessary for inflammation resolution in ARDS. . JCI Insight 9::e173440
     [Crossref] [Google Scholar]
  111. 111.
    Dashkevich A, Heilmann C, Kayser G, Germann M, Beyersdorf F, et al. 2010.. Lymph angiogenesis after lung transplantation and relation to acute organ rejection in humans. . Ann. Thorac. Surg. 90::406–11
     [Crossref] [Google Scholar]
  112. 112.
    Dietrich T, Bock F, Yuen D, Hos D, Bachmann BO, et al. 2009.. Cutting edge: lymphatic vessels, not blood vessels, primarily mediate immune rejections after transplantation. . J. Immunol. 184::535–39
     [Crossref] [Google Scholar]
  113. 113.
    Cui Y, Liu K, Lamattina AM, Visner G, El-Chemaly S. 2017.. Lymphatic vessels: the next frontier in lung transplant. . Ann. Am. Thorac. Soc. 14::S226–32
     [Crossref] [Google Scholar]
  114. 114.
    Cui Y, Liu K, Monzon-Medina ME, Padera RF, Wang H, et al. 2015.. Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection. . J. Clin. Investig. 125::4255–68
     [Crossref] [Google Scholar]
  115. 115.
    Outtz Reed H, Wang L, Kahn ML, Hancock WW. 2020.. Donor-host lymphatic anastomosis after murine lung transplantation. . Transplantation 104::511–15
     [Crossref] [Google Scholar]
  116. 116.
    Churchill MJ, du Bois H, Heim TA, Mudianto T, Steele MM, et al. 2022.. Infection-induced lymphatic zippering restricts fluid transport and viral dissemination from skin. . J. Exp. Med. 219::e20211830
     [Crossref] [Google Scholar]
  117. 117.
    Pflicke H, Sixt M. 2009.. Preformed portals facilitate dendritic cell entry into afferent lymphatic vessels. . J. Exp. Med. 206::2925–35
     [Crossref] [Google Scholar]
  118. 118.
    Trivedi A, Lu TM, Summers B, Kim K, Rhee AJ, et al. 2024.. Lung lymphatic endothelial cells undergo inflammatory and prothrombotic changes in a model of chronic obstructive pulmonary disease. . Front. Cell Dev. Biol. 12::1344070
     [Crossref] [Google Scholar]
  119. 119.
    Gkountidi AO, Garnier L, Dubrot J, Angelillo J, Harle G, et al. 2021.. MHC class II antigen presentation by lymphatic endothelial cells in tumors promotes intratumoral regulatory T cell-suppressive functions. . Cancer Immunol. Res. 9::748–64
     [Crossref] [Google Scholar]
  120. 120.
    Dubrot J, Duraes FV, Potin L, Capotosti F, Brighouse D, 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
     [Crossref] [Google Scholar]
  121. 121.
    Dubrot J, Duraes FV, Harlé G, Schlaeppi A, Brighouse D, et al. 2018.. Absence of MHC-II expression by lymph node stromal cells results in autoimmunity. . Life Sci. Alliance 1::e201800164
     [Crossref] [Google Scholar]
  122. 122.
    Li CY, Park HJ, Shin J, Baik JE, Mehrara BJ, Kataru RP. 2022.. Tumor-associated lymphatics upregulate MHC-II to suppress tumor-infiltrating lymphocytes. . Int. J. Mol. Sci. 23::13470
     [Crossref] [Google Scholar]
  123. 123.
    Tamburini BA, Burchill MA, Kedl RM. 2014.. Antigen capture and archiving by lymphatic endothelial cells following vaccination or viral infection. . Nat. Commun. 5::3989
     [Crossref] [Google Scholar]
  124. 124.
    Kedl RM, Lindsay RS, Finlon JM, Lucas ED, Friedman RS, Tamburini BAJ. 2017.. Migratory dendritic cells acquire and present lymphatic endothelial cell-archived antigens during lymph node contraction. . Nat. Commun. 8::2034
     [Crossref] [Google Scholar]
  125. 125.
    Podgrabinska S, Kamalu O, Mayer L, Shimaoka M, Snoeck H, et al. 2009.. Inflamed lymphatic endothelium suppresses dendritic cell maturation and function via Mac-1/ICAM-1-dependent mechanism. . J. Immunol. 183::1767–79
     [Crossref] [Google Scholar]
  126. 126.
    Shinoda K, Hirahara K, Iinuma T, Ichikawa T, Suzuki AS, et al. 2016.. Thy1+IL-7+ lymphatic endothelial cells in iBALT provide a survival niche for memory T-helper cells in allergic airway inflammation. . PNAS 113::E2842–51
     [Crossref] [Google Scholar]
  127. 127.
    Kataru RP, Jung K, Jang C, Yang H, Schwendener RA, et al. 2009.. Critical role of CD11b+ macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution. . Blood 113::5650–59
     [Crossref] [Google Scholar]
  128. 128.
    Shin K, Kataru RP, Park HJ, Kwon BI, Kim TW, et al. 2015.. TH2 cells and their cytokines regulate formation and function of lymphatic vessels. . Nat. Commun. 6::6196
     [Crossref] [Google Scholar]
  129. 129.
    Christiansen AJ, Dieterich LC, Ohs I, Bachmann SB, Bianchi R, et al. 2016.. Lymphatic endothelial cells attenuate inflammation via suppression of dendritic cell maturation. . Oncotarget 7::39421–35
     [Crossref] [Google Scholar]
  130. 130.
    Hirosue S, Vokali E, Raghavan VR, Rincon-Restrepo M, Lund AW, 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
     [Crossref] [Google Scholar]
  131. 131.
    Lund AW, Duraes FV, Hirosue S, Raghavan VR, Nembrini C, et al. 2012.. VEGF-C promotes immune tolerance in B16 melanomas and cross-presentation of tumor antigen by lymph node lymphatics. . Cell Rep. 1::191–99
     [Crossref] [Google Scholar]
  132. 132.
    Tewalt EF, Cohen JN, Rouhani SJ, Guidi CJ, Qiao H, et al. 2012.. Lymphatic endothelial cells induce tolerance via PD-L1 and lack of costimulation leading to high-level PD-1 expression on CD8 T cells. . Blood 120::4772–82
     [Crossref] [Google Scholar]
  133. 133.
    Dieterich LC, Ikenberg K, Cetintas T, Kapaklikaya K, Hutmacher C, Detmar M. 2017.. Tumor-associated lymphatic vessels upregulate PDL1 to inhibit T-cell activation. . Front. Immunol. 8::66
     [Crossref] [Google Scholar]
  134. 134.
    Vokali E, Yu SS, Hirosue S, Rinçon-Restrepo M, Duraes FV, et al. 2020.. Lymphatic endothelial cells prime naïve CD8. . Nat. Commun. 11::538
     [Crossref] [Google Scholar]
  135. 135.
    Liu X, De la Cruz E, Gu X, Balint L, Oxendine-Burns M, et al. 2020.. Lymphoangiocrine signals promote cardiac growth and repair. . Nature 588::705–11
     [Crossref] [Google Scholar]
  136. 136.
    Gur-Cohen S, Yang H, Baksh SC, Miao Y, Levorse J, et al. 2019.. Stem cell-driven lymphatic remodeling coordinates tissue regeneration. . Science 366::1218–25
     [Crossref] [Google Scholar]
  137. 137.
    Niec RE, Chu T, Schernthanner M, Gur-Cohen S, Hidalgo L, et al. 2022.. Lymphatics act as a signaling hub to regulate intestinal stem cell activity. . Cell Stem Cell 29::1067–82.e18
     [Crossref] [Google Scholar]
  138. 138.
    Harrison MR, Feng X, Mo G, Aguayo A, Villafuerte J, et al. 2019.. Late developing cardiac lymphatic vasculature supports adult zebrafish heart function and regeneration. . eLife 8::e42762
     [Crossref] [Google Scholar]
  139. 139.
    Vieira JM, Norman S, Villa del Campo C, Cahill TJ, Barnette DN, et al. 2018.. The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction. . J. Clin. Investig. 128::3402–12
     [Crossref] [Google Scholar]
  140. 140.
    Palikuqi B, Rispal J, Reyes EA, Vaka D, Boffelli D, Klein O. 2022.. Lymphangiocrine signals are required for proper intestinal repair after cytotoxic injury. . Cell Stem Cell 29::1262–72.e5
     [Crossref] [Google Scholar]
  141. 141.
    Biswas L, Chen J, De Angelis J, Singh A, Owen-Woods C, et al. 2023.. Lymphatic vessels in bone support regeneration after injury. . Cell 186::382–97.e24
     [Crossref] [Google Scholar]
  142. 142.
    Stranford S, Ruddle NH. 2012.. Follicular dendritic cells, conduits, lymphatic vessels, and high endothelial venules in tertiary lymphoid organs: parallels with lymph node stroma. . Front. Immunol. 3::350
     [Crossref] [Google Scholar]
  143. 143.
    Baluk P, Adams A, Phillips K, Feng J, Hong YK, et al. 2014.. Preferential lymphatic growth in bronchus-associated lymphoid tissue in sustained lung inflammation. . Am. J. Pathol. 184::1577–92
     [Crossref] [Google Scholar]
  144. 144.
    Ruddle NH. 2014.. Lymphatic vessels and tertiary lymphoid organs. . J. Clin. Investig. 124::953–59
     [Crossref] [Google Scholar]
  145. 145.
    Jones GW, Hill DG, Jones SA. 2016.. Understanding immune cells in tertiary lymphoid organ development: it is all starting to come together. . Front. Immunol. 7::401
     [Crossref] [Google Scholar]
  146. 146.
    Aloisi F, Pujol-Borrell R. 2006.. Lymphoid neogenesis in chronic inflammatory diseases. . Nat. Rev. Immunol. 6::205–17
     [Crossref] [Google Scholar]
  147. 147.
    Hwang JY, Silva-Sanchez A, Carragher DM, Garcia-Hernandez ML, Rangel-Moreno J, Randall TD. 2020.. Inducible bronchus-associated lymphoid tissue (iBALT) attenuates pulmonary pathology in a mouse model of allergic airway disease. . Front. Immunol. 11::570661
     [Crossref] [Google Scholar]
  148. 148.
    Elliot JG, Jensen CM, Mutavdzic S, Lamb JP, Carroll NG, James AL. 2004.. Aggregations of lymphoid cells in the airways of nonsmokers, smokers, and subjects with asthma. . Am. J. Respir. Crit. Care Med. 169::712–18
     [Crossref] [Google Scholar]
  149. 149.
    Lee JJ, McGarry MP, Farmer SC, Denzler KL, Larson KA, et al. 1997.. Interleukin-5 expression in the lung epithelium of transgenic mice leads to pulmonary changes pathognomonic of asthma. . J. Exp. Med. 185::2143–56
     [Crossref] [Google Scholar]
  150. 150.
    Gosman MM, Willemse BW, Jansen DF, Lapperre TS, van Schadewijk A, et al. 2006.. Increased number of B-cells in bronchial biopsies in COPD. . Eur. Respir. J. 27::60–64
     [Crossref] [Google Scholar]
  151. 151.
    Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, et al. 2004.. The nature of small-airway obstruction in chronic obstructive pulmonary disease. . N. Engl. J. Med. 350::2645–53
     [Crossref] [Google Scholar]
  152. 152.
    Rangel-Moreno J, Hartson L, Navarro C, Gaxiola M, Selman M, Randall TD. 2006.. Inducible bronchus-associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis. . J. Clin. Investig. 116::3183–94
     [Crossref] [Google Scholar]
  153. 153.
    Hasegawa T, Iacono A, Yousem SA. 1999.. The significance of bronchus-associated lymphoid tissue in human lung transplantation: is there an association with acute and chronic rejection?. Transplantation 67::381–85
     [Crossref] [Google Scholar]
  154. 154.
    Foo SY, Phipps S. 2010.. Regulation of inducible BALT formation and contribution to immunity and pathology. . Mucosal Immunol. 3::537–44
     [Crossref] [Google Scholar]
  155. 155.
    Wiley JA, Richert LE, Swain SD, Harmsen A, Barnard DL, et al. 2009.. Inducible bronchus-associated lymphoid tissue elicited by a protein cage nanoparticle enhances protection in mice against diverse respiratory viruses. . PLOS ONE 4::e7142
     [Crossref] [Google Scholar]
  156. 156.
    Ramakrishnan L. 2012.. Revisiting the role of the granuloma in tuberculosis. . Nat. Rev. Immunol. 12::352–66
     [Crossref] [Google Scholar]
  157. 157.
    Feghali-Bostwick CA, Gadgil AS, Otterbein LE, Pilewski JM, Stoner MW, et al. 2008.. Autoantibodies in patients with chronic obstructive pulmonary disease. . Am. J. Respir. Crit. Care Med. 177::156–63
     [Crossref] [Google Scholar]
  158. 158.
    Demoor T, Bracke KR, Maes T, Vandooren B, Elewaut D, et al. 2009.. Role of lymphotoxin-α in cigarette smoke-induced inflammation and lymphoid neogenesis. . Eur. Respir. J. 34::405–16
     [Crossref] [Google Scholar]
  159. 159.
    Caramori G, Ruggeri P, Di Stefano A, Mumby S, Girbino G, et al. 2018.. Autoimmunity and COPD: clinical implications. . Chest 153::1424–31
     [Crossref] [Google Scholar]
  160. 160.
    Silva-Sanchez A, Randall TD. 2020.. Role of iBALT in respiratory immunity. . Curr. Top. Microbiol. Immunol. 426::21–43
     [Google Scholar]
  161. 161.
    Prop J, Wildevuur CR, Nieuwenhuis P. 1985.. Lung allograft rejection in the rat. II. Specific immunological properties of lung grafts. . Transplantation 40::126–31
     [Crossref] [Google Scholar]
  162. 162.
    Bery AI, Hachem RR. 2020.. Antibody-mediated rejection after lung transplantation. . Ann. Transl. Med. 8::411
     [Crossref] [Google Scholar]
  163. 163.
    Li W, Gauthier JM, Higashikubo R, Hsiao HM, Tanaka S, et al. 2019.. Bronchus-associated lymphoid tissue-resident Foxp3+ T lymphocytes prevent antibody-mediated lung rejection. . J. Clin. Investig. 129::556–68
     [Crossref] [Google Scholar]
  164. 164.
    Li W, Bribriesco AC, Nava RG, Brescia AA, Ibricevic A, et al. 2012.. Lung transplant acceptance is facilitated by early events in the graft and is associated with lymphoid neogenesis. . Mucosal Immunol. 5::544–54
     [Crossref] [Google Scholar]
  165. 165.
    Tanaka S, Gauthier JM, Fuchs A, Li W, Tong AY, et al. 2020.. IL-22 is required for the induction of bronchus-associated lymphoid tissue in tolerant lung allografts. . Am. J. Transplant. 20::1251–61
     [Crossref] [Google Scholar]
  166. 166.
    Terada Y, Li W, Shepherd HM, Takahashi T, Yokoyama Y, et al. 2024.. Smoking exposure-induced bronchus-associated lymphoid tissue in donor lungs does not prevent tolerance induction after transplantation. . Am. J. Transplant. 24::280–92
     [Crossref] [Google Scholar]
  167. 167.
    Czepielewski RS, Erlich EC, Onufer EJ, Young S, Saunders BT, et al. 2021.. Ileitis-associated tertiary lymphoid organs arise at lymphatic valves and impede mesenteric lymph flow in response to tumor necrosis factor. . Immunity 54::2795–811.e9
     [Crossref] [Google Scholar]
  168. 168.
    Amezcua Vesely MC, Pallis P, Bielecki P, Low JS, Zhao J, et al. 2019.. Effector TH17 cells give rise to long-lived TRM cells that are essential for an immediate response against bacterial infection. . Cell 178::1176–88.e15
     [Crossref] [Google Scholar]
  169. 169.
    Janer J, Lassus P, Haglund C, Paavonen K, Alitalo K, Andersson S. 2006.. Pulmonary vascular endothelial growth factor-C in development and lung injury in preterm infants. . Am. J. Respir. Crit. Care Med. 174::326–30
     [Crossref] [Google Scholar]
  170. 170.
    Albertine KH. 2015.. Utility of large-animal models of BPD: chronically ventilated preterm lambs. . Am. J. Physiol. Lung Cell. Mol. Physiol. 308::L983–1001
     [Crossref] [Google Scholar]
  171. 171.
    Itkin M, Chidekel A, Ryan KA, Rabinowitz D. 2020.. Abnormal pulmonary lymphatic flow in patients with paediatric pulmonary lymphatic disorders: diagnosis and treatment. . Paediatr. Respir. Rev. 36::15–24
     [Google Scholar]
  172. 172.
    Shankar N, Thapa S, Shrestha AK, Sarkar P, Gaber MW, et al. 2023.. Hyperoxia disrupts lung lymphatic homeostasis in neonatal mice. . Antioxidants 12::620
     [Crossref] [Google Scholar]
  173. 173.
    Khan S, Smith CL, Pinto EM, Taha DK, Gibbs KA, et al. 2023.. Effect of positive pressure ventilation on lymphatic flow in pediatric patients. . J. Perinatol. 43::1079–81
     [Crossref] [Google Scholar]
  174. 174.
    Thibeault DW, Black P, Taboada E. 2002.. Fetal hydrops and familial pulmonary lymphatic hypoplasia. . Am. J. Perinatol. 19::323–31
     [Crossref] [Google Scholar]
  175. 175.
    Thibeault DW, Zalles C, Wickstrom E. 1995.. Familial pulmonary lymphatic hypoplasia associated with fetal pleural effusions. . J. Pediatr. 127::979–83
     [Crossref] [Google Scholar]
  176. 176.
    Esther CR Jr., Barker PM. 2004.. Pulmonary lymphangiectasia: diagnosis and clinical course. . Pediatr. Pulmonol. 38::308–13
     [Crossref] [Google Scholar]
  177. 177.
    Ozeki M, Fukao T. 2019.. Generalized lymphatic anomaly and Gorham–Stout disease: overview and recent insights. . Adv. Wound Care 8::230–45
     [Crossref] [Google Scholar]
  178. 178.
    Ricci KW, Hammill AM, Mobberley-Schuman P, Nelson SC, Blatt J, et al. 2019.. Efficacy of systemic sirolimus in the treatment of generalized lymphatic anomaly and Gorham–Stout disease. . Pediatr. Blood Cancer 66::e27614
     [Crossref] [Google Scholar]
  179. 179.
    Adams DM, Trenor CC III, Hammill AM, Vinks AA, Patel MN, et al. 2016.. Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies. . Pediatrics 137::e20153257
     [Crossref] [Google Scholar]
  180. 180.
    Engel ER, Hammill A, Adams D, Phillips RJ, Jeng M, et al. 2023.. Response to sirolimus in capillary lymphatic venous malformations and associated syndromes: impact on symptomatology, quality of life, and radiographic response. . Pediatr. Blood Cancer 70::e30215
     [Crossref] [Google Scholar]
  181. 181.
    Seront E, Van Damme A, Boon LM, Vikkula M. 2019.. Rapamycin and treatment of venous malformations. . Curr. Opin. Hematol. 26::185–92
     [Crossref] [Google Scholar]
  182. 182.
    Baluk P, Yao LC, Flores JC, Choi D, Hong YK, McDonald DM. 2017.. Rapamycin reversal of VEGF-C–driven lymphatic anomalies in the respiratory tract. . JCI Insight 2::e90103
     [Crossref] [Google Scholar]
  183. 183.
    Baluk P, Yao LC, Feng J, Romano T, Jung SS, 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]
  184. 184.
    Yao LC, Baluk P, Feng J, McDonald DM. 2010.. Steroid-resistant lymphatic remodeling in chronically inflamed mouse airways. . Am. J. Pathol. 176::1525–41
     [Crossref] [Google Scholar]
  185. 185.
    Valeyre D, Nunes H, Bernaudin JF. 2014.. Advanced pulmonary sarcoidosis. . Curr. Opin. Pulm. Med. 20::488–95
     [Crossref] [Google Scholar]
  186. 186.
    El Jammal T, Pavic M, Gerfaud-Valentin M, Jamilloux Y, Sève P. 2020.. Sarcoidosis and cancer: a complex relationship. . Front. Med. 7::594118
     [Crossref] [Google Scholar]
  187. 187.
    Rao DA, Dellaripa PF. 2013.. Extrapulmonary manifestations of sarcoidosis. . Rheum. Dis. Clin. North Am. 39::277–97
     [Crossref] [Google Scholar]
  188. 188.
    Rosen Y, Vuletin JC, Pertschuk LP, Silverstein E. 1979.. Sarcoidosis: from the pathologist's vantage point. . Pathol. Annu. 14:(Part 1):405–39
     [Google Scholar]
  189. 189.
    Kambouchner M, Pirici D, Uhl JF, Mogoanta L, Valeyre D, Bernaudin JF. 2011.. Lymphatic and blood microvasculature organisation in pulmonary sarcoid granulomas. . Eur. Respir. J. 37::835–40
     [Crossref] [Google Scholar]
  190. 190.
    Patterson KC, Queval CJ, Gutierrez MG. 2019.. Granulomatous inflammation in tuberculosis and sarcoidosis: Does the lymphatic system contribute to disease?. Bioessays 41::e1900086
     [Crossref] [Google Scholar]
  191. 191.
    Biener L, Kruse J, Tuleta I, Pizarro C, Kreuter M, et al. 2021.. Association of proangiogenic and profibrotic serum markers with lung function and quality of life in sarcoidosis. . PLOS ONE 16::e0247197
     [Crossref] [Google Scholar]
  192. 192.
    Liu Y, Liu Y, Su L, Jiang SJ. 2014.. Recipient-related clinical risk factors for primary graft dysfunction after lung transplantation: a systematic review and meta-analysis. . PLOS ONE 9::e92773
     [Crossref] [Google Scholar]
  193. 193.
    Chambers DC, Yusen RD, Cherikh WS, Goldfarb SB, Kucheryavaya AY, et al. 2017.. The registry of the International Society for Heart and Lung Transplantation: thirty-fourth adult heart transplantation report—2017; focus theme: allograft ischemic time. . J. Heart Lung Transplant. 36::1047–59
     [Crossref] [Google Scholar]
  194. 194.
    Boehler A. 2003.. Update on cystic fibrosis: selected aspects related to lung transplantation. . Swiss Med. Wkly. 133::111–17
     [Google Scholar]
  195. 195.
    Trulock EP, Christie JD, Edwards LB, Boucek MM, Aurora P, et al. 2007.. Registry of the International Society for Heart and Lung Transplantation: twenty-fourth official adult lung and heart–lung transplantation report—2007. . J. Heart Lung Transplant. 26::782–95
     [Crossref] [Google Scholar]
  196. 196.
    Ruggiero R, Fietsam R Jr., Thomas GA, Muz J, Farris RH, et al. 1994.. Detection of canine allograft lung rejection by pulmonary lymphoscintigraphy. . J. Thorac. Cardiovasc. Surg. 108::253–58
     [Crossref] [Google Scholar]
  197. 197.
    Tesar BM, Jiang D, Liang J, Palmer SM, Noble PW, Goldstein DR. 2006.. The role of hyaluronan degradation products as innate alloimmune agonists. . Am. J. Transplant. 6::2622–35
     [Crossref] [Google Scholar]
  198. 198.
    Todd JL, Wang X, Sugimoto S, Kennedy VE, Zhang HL, et al. 2014.. Hyaluronan contributes to bronchiolitis obliterans syndrome and stimulates lung allograft rejection through activation of innate immunity. . Am. J. Respir. Crit. Care Med. 189::556–66
     [Crossref] [Google Scholar]
  199. 199.
    Krupnick AS, Lin X, Li W, Higashikubo R, Zinselmeyer BH, et al. 2014.. Central memory CD8+ T lymphocytes mediate lung allograft acceptance. . J. Clin. Investig. 124::1130–43
     [Crossref] [Google Scholar]
  200. 200.
    Gelman AE, Li W, Richardson SB, Zinselmeyer BH, Lai J, et al. 2009.. Cutting edge: Acute lung allograft rejection is independent of secondary lymphoid organs. . J. Immunol. 182::3969–73
     [Crossref] [Google Scholar]
  201. 201.
    Ganchua SKC, White AG, Klein EC, Flynn JL. 2020.. Lymph nodes—the neglected battlefield in tuberculosis. . PLOS Pathog. 16::e1008632
     [Crossref] [Google Scholar]
  202. 202.
    Basaraba RJ, Smith EE, Shanley CA, Orme IM. 2006.. Pulmonary lymphatics are primary sites of Mycobacterium tuberculosis infection in guinea pigs infected by aerosol. . Infect. Immun. 74::5397–401
     [Crossref] [Google Scholar]
  203. 203.
    Kraft SL, Dailey D, Kovach M, Stasiak KL, Bennett J, et al. 2004.. Magnetic resonance imaging of pulmonary lesions in guinea pigs infected with Mycobacterium tuberculosis. . Infect. Immun. 72::5963–71
     [Crossref] [Google Scholar]
  204. 204.
    Chackerian AA, Alt JM, Perera TV, Dascher CC, Behar SM. 2002.. Dissemination of Mycobacterium tuberculosis is influenced by host factors and precedes the initiation of T-cell immunity. . Infect. Immun. 70::4501–9
     [Crossref] [Google Scholar]
  205. 205.
    Tian T, Woodworth J, Sköld M, Behar SM. 2005.. In vivo depletion of CD11c+ cells delays the CD4+ T cell response to Mycobacterium tuberculosis and exacerbates the outcome of infection. . J. Immunol. 175::3268–72
     [Crossref] [Google Scholar]
  206. 206.
    Harding J, Ritter A, Rayasam A, Fabry Z, Sandor M. 2015.. Lymphangiogenesis is induced by mycobacterial granulomas via vascular endothelial growth factor receptor-3 and supports systemic T-cell responses against mycobacterial antigen. . Am. J. Pathol. 185::432–45
     [Crossref] [Google Scholar]
  207. 207.
    Kumar NP, Banurekha VV, Nair D, Babu S. 2016.. Circulating angiogenic factors as biomarkers of disease severity and bacterial burden in pulmonary tuberculosis. . PLOS ONE 11::e0146318
     [Crossref] [Google Scholar]
  208. 208.
    Ge J, Shao H, Ding H, Huang Y, Wu X, et al. 2024.. Single cell analysis of lung lymphatic endothelial cells and lymphatic responses during influenza infection. . J. Respir. Biol. Transl. Med. 1::10003
     [Google Scholar]
  209. 209.
    MacDonald ME, Weathered RK, Stewart EC, Magold AI, Mukherjee A, et al. 2022.. Lymphatic coagulation and neutrophil extracellular traps in lung-draining lymph nodes of COVID-19 decedents. . Blood Adv. 6::6249–62
     [Crossref] [Google Scholar]
  210. 210.
    Gavrilovskaya IN, Gorbunova EE, Mackow ER. 2012.. Andes virus infection of lymphatic endothelial cells causes giant cell and enhanced permeability responses that are rapamycin and vascular endothelial growth factor C sensitive. . J. Virol. 86::8765–72
     [Crossref] [Google Scholar]
  211. 211.
    Mackow ER, Gorbunova EE, Dalrymple NA, Gavrilovskaya IN. 2013.. Role of vascular and lymphatic endothelial cells in hantavirus pulmonary syndrome suggests targeted therapeutic approaches. . Lymphat. Res. Biol. 11::128–35
     [Crossref] [Google Scholar]
  212. 212.
    Vestbo J, Hurd SS, Agustí AG, Jones PW, Vogelmeier C, et al. 2013.. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. . Am. J. Respir. Crit. Care Med. 187::347–65
     [Crossref] [Google Scholar]
  213. 213.
    Hogg JC. 2006.. Why does airway inflammation persist after the smoking stops?. Thorax 61::96–97
     [Crossref] [Google Scholar]
  214. 214.
    Hardavella G, Tzortzaki EG, Siozopoulou V, Galanis P, Vlachaki E, et al. 2012.. Lymphangiogenesis in COPD: another link in the pathogenesis of the disease. . Respir. Med. 106::687–93
     [Crossref] [Google Scholar]
  215. 215.
    Hogg JC, Paré PD, Hackett TL. 2017.. The contribution of small airway obstruction to the pathogenesis of chronic obstructive pulmonary disease. . Physiol. Rev. 97::529–52
     [Crossref] [Google Scholar]
  216. 216.
    Rojas-Quintero J, Ochsner SA, New F, Divakar P, Yang CX, et al. 2024.. Spatial transcriptomics resolve an emphysema-specific lymphoid follicle B cell signature in chronic obstructive pulmonary disease. . Am. J. Respir. Crit. Care Med. 209::4858
     [Crossref] [Google Scholar]
  217. 217.
    Sullivan JL, Bagevalu B, Glass C, Sholl L, Kraft M, et al. 2019.. B cell-adaptive immune profile in emphysema-predominant chronic obstructive pulmonary disease. . Am. J. Respir. Crit. Care Med. 200::1434–39
     [Crossref] [Google Scholar]
  218. 218.
    Lara AR, Cosgrove GP, Janssen WJ, Huie TJ, Burnham EL, et al. 2012.. Increased lymphatic vessel length is associated with the fibroblast reticulum and disease severity in usual interstitial pneumonia and nonspecific interstitial pneumonia. . Chest 142::1569–76
     [Crossref] [Google Scholar]
  219. 219.
    Yamashita M, Iwama N, Date F, Chiba R, Ebina M, et al. 2009.. Characterization of lymphangiogenesis in various stages of idiopathic diffuse alveolar damage. . Hum. Pathol. 40::542–51
     [Crossref] [Google Scholar]
  220. 220.
    Ebina M, Shibata N, Ohta H, Hisata S, Tamada T, et al. 2010.. The disappearance of subpleural and interlobular lymphatics in idiopathic pulmonary fibrosis. . Lymphat. Res. Biol. 8::199–207
     [Crossref] [Google Scholar]
  221. 221.
    Schraufnagel DE. 2020.. The health effects of ultrafine particles. . Exp. Mol. Med. 52::311–17
     [Crossref] [Google Scholar]
  222. 222.
    Leak LV. 1980.. Lymphatic removal of fluids and particles in the mammalian lung. . Environ. Health Perspect. 35::55–75
     [Crossref] [Google Scholar]
  223. 223.
    Miura T, Shimada T, Tanaka K, Chujo M, Uchida Y. 2000.. Lymphatic drainage of carbon particles injected into the pleural cavity of the monkey, as studied by video-assisted thoracoscopy and electron microscopy. . J. Thorac. Cardiovasc. Surg. 120::437–47
     [Crossref] [Google Scholar]
  224. 224.
    Lauweryns JM, Baert JH. 1974.. The role of the pulmonary lymphatics in the defenses of the distal lung: morphological and experimental studies of the transport mechanisms of intratracheally instillated particles. . Ann. N. Y. Acad. Sci. 221::244–75
     [Crossref] [Google Scholar]
  225. 225.
    Ural BB, Caron DP, Dogra P, Wells SB, Szabo PA, et al. 2022.. Inhaled particulate accumulation with age impairs immune function and architecture in human lung lymph nodes. . Nat. Med. 28::2622–32
     [Crossref] [Google Scholar]
  226. 226.
    Viúdez-Pareja C, Kreft E, García-Caballero M. 2023.. Immunomodulatory properties of the lymphatic endothelium in the tumor microenvironment. . Front. Immunol. 14::1235812
     [Crossref] [Google Scholar]
  227. 227.
    Koukourakis MI, Giatromanolaki A, Sivridis E, Simopoulos C, Gatter KC, et al. 2005.. LYVE-1 immunohistochemical assessment of lymphangiogenesis in endometrial and lung cancer. . J. Clin. Pathol. 58::202–6
     [Crossref] [Google Scholar]
  228. 228.
    Renyi-Vamos F, Tovari J, Fillinger J, Timar J, Paku S, et al. 2005.. Lymphangiogenesis correlates with lymph node metastasis, prognosis, and angiogenic phenotype in human non-small cell lung cancer. . Clin. Cancer Res. 11::7344–53
     [Crossref] [Google Scholar]
  229. 229.
    Kajita T, Ohta Y, Kimura K, Tamura M, Tanaka Y, et al. 2001.. The expression of vascular endothelial growth factor C and its receptors in non-small cell lung cancer. . Br. J. Cancer 85::255–60
     [Crossref] [Google Scholar]
  230. 230.
    Ishii H, Yazawa T, Sato H, Suzuki T, Ikeda M, et al. 2004.. Enhancement of pleural dissemination and lymph node metastasis of intrathoracic lung cancer cells by vascular endothelial growth factors (VEGFs). . Lung Cancer 45::325–37
     [Crossref] [Google Scholar]
  231. 231.
    Hu J, Ye H, Fu A, Chen X, Wang Y, et al. 2010.. Deguelin—an inhibitor to tumor lymphangiogenesis and lymphatic metastasis by downregulation of vascular endothelial cell growth factor-D in lung tumor model. . Int. J. Cancer 127::2455–66
     [Crossref] [Google Scholar]
  232. 232.
    Saintigny P, Kambouchner M, Ly M, Gomes N, Sainte-Catherine O, et al. 2007.. Vascular endothelial growth factor-C and its receptor VEGFR-3 in non-small-cell lung cancer: concurrent expression in cancer cells from primary tumour and metastatic lymph node. . Lung Cancer 58::205–13
     [Crossref] [Google Scholar]
  233. 233.
    Bogos K, Renyi-Vamos F, Dobos J, Kenessey I, Tovari J, et al. 2009.. High VEGFR-3-positive circulating lymphatic/vascular endothelial progenitor cell level is associated with poor prognosis in human small cell lung cancer. . Clin. Cancer Res. 15::1741–46
     [Crossref] [Google Scholar]
  234. 234.
    Zhang S, Wang H, Xu Z, Bai Y, Xu L. 2020.. Lymphatic metastasis of NSCLC involves chemotaxis effects of lymphatic endothelial cells through the CCR7–CCL21 axis modulated by TNF-α. . Genes 11::1309
     [Crossref] [Google Scholar]
  235. 235.
    Nakamura ES, Koizumi K, Kobayashi M, Saiki I. 2004.. Inhibition of lymphangiogenesis-related properties of murine lymphatic endothelial cells and lymph node metastasis of lung cancer by the matrix metalloproteinase inhibitor MMI270. . Cancer Sci. 95::25–31
     [Crossref] [Google Scholar]
  236. 236.
    Carsillo T, Astrinidis A, Henske EP. 2000.. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. . PNAS 97::6085–90
     [Crossref] [Google Scholar]
  237. 237.
    Cudzilo CJ, Szczesniak RD, Brody AS, Rattan MS, Krueger DA, et al. 2013.. Lymphangioleiomyomatosis screening in women with tuberous sclerosis. . Chest 144::578–85
     [Crossref] [Google Scholar]
  238. 238.
    Muzykewicz DA, Sharma A, Muse V, Numis AL, Rajagopal J, Thiele EA. 2009.. TSC1 and TSC2 mutations in patients with lymphangioleiomyomatosis and tuberous sclerosis complex. . J. Med. Genet. 46::465–68
     [Crossref] [Google Scholar]
  239. 239.
    Adriaensen ME, Schaefer-Prokop CM, Duyndam DA, Zonnenberg BA, Prokop M. 2011.. Radiological evidence of lymphangioleiomyomatosis in female and male patients with tuberous sclerosis complex. . Clin. Radiol. 66::625–28
     [Crossref] [Google Scholar]
  240. 240.
    Pacheco-Rodriguez G, Kumaki F, Steagall WK, Zhang Y, Ikeda Y, et al. 2009.. Chemokine-enhanced chemotaxis of lymphangioleiomyomatosis cells with mutations in the tumor suppressor TSC2 gene. . J. Immunol. 182::1270–77
     [Crossref] [Google Scholar]
  241. 241.
    Pacheco-Rodriguez G, Glasgow CG, Ikeda Y, Steagall WK, Yu ZX, et al. 2022.. A mixed blood-lymphatic endothelial cell phenotype in lymphangioleiomyomatosis and idiopathic pulmonary fibrosis but not in Kaposi's sarcoma or tuberous sclerosis complex. . Am. J. Respir. Cell Mol. Biol. 66::337–40
     [Crossref] [Google Scholar]
  242. 242.
    Steagall WK, Pacheco-Rodriguez G, Darling TN, Torre O, Harari S, Moss J. 2018.. The lymphangioleiomyomatosis lung cell and its human cell models. . Am. J. Respir. Cell Mol. Biol. 58::678–83
     [Crossref] [Google Scholar]
  243. 243.
    Young L, Lee HS, Inoue Y, Moss J, Singer LG, et al. 2013.. Serum VEGF-D concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial. . Lancet Respir. Med. 1::445–52
     [Crossref] [Google Scholar]
  244. 244.
    Du Y, Guo M, Wu Y, Wagner A, Perl AK, et al. 2023.. Lymphangioleiomyomatosis (LAM) cell atlas. . Thorax 78::85–87
     [Crossref] [Google Scholar]
  245. 245.
    Nishino K, Yoshimatsu Y, Muramatsu T, Sekimoto Y, Mitani K, et al. 2021.. Isolation and characterisation of lymphatic endothelial cells from lung tissues affected by lymphangioleiomyomatosis. . Sci. Rep. 11::8406
     [Crossref] [Google Scholar]
  246. 246.
    Kumasaka T, Seyama K, Mitani K, Sato T, Souma S, et al. 2004.. Lymphangiogenesis in lymphangioleiomyomatosis: its implication in the progression of lymphangioleiomyomatosis. . Am. J. Surg. Pathol. 28::1007–16
     [Crossref] [Google Scholar]
  247. 247.
    Davis JM, Hyjek E, Husain AN, Shen L, Jones J, Schuger LA. 2013.. Lymphatic endothelial differentiation in pulmonary lymphangioleiomyomatosis cells. . J. Histochem. Cytochem. 61::580–90
     [Crossref] [Google Scholar]
  248. 248.
    Yue M, Pacheco G, Cheng T, Li J, Wang Y, et al. 2016.. Evidence supporting a lymphatic endothelium origin for angiomyolipoma, a TSC2− tumor related to lymphangioleiomyomatosis. . Am. J. Pathol. 186::1825–36
     [Crossref] [Google Scholar]
  249. 249.
    Guo M, Yu JJ, Perl AK, Wikenheiser-Brokamp KA, Riccetti M, et al. 2020.. Single-cell transcriptomic analysis identifies a unique pulmonary lymphangioleiomyomatosis cell. . Am. J. Respir. Crit. Care Med. 202::1373–87
     [Crossref] [Google Scholar]
  250. 250.
    Mäkinen T, Boon LM, Vikkula M, Alitalo K. 2021.. Lymphatic malformations: genetics, mechanisms and therapeutic strategies. . Circ. Res. 129::136–54
     [Crossref] [Google Scholar]
  251. 251.
    Trenor CC III, Chaudry G. 2014.. Complex lymphatic anomalies. . Semin. Pediatr. Surg. 23::186–90
     [Crossref] [Google Scholar]
  252. 252.
    Ozeki M, Fujino A, Matsuoka K, Nosaka S, Kuroda T, Fukao T. 2016.. Clinical features and prognosis of generalized lymphatic anomaly, kaposiform lymphangiomatosis, and Gorham–Stout disease. . Pediatr. Blood Cancer 63::832–38
     [Crossref] [Google Scholar]
  253. 253.
    Iacobas I, Adams DM, Pimpalwar S, Phung T, Blei F, et al. 2020.. Multidisciplinary guidelines for initial evaluation of complicated lymphatic anomalies—expert opinion consensus. . Pediatr. Blood Cancer 67::e28036
     [Crossref] [Google Scholar]
  254. 254.
    Adams DM, Ricci KW. 2019.. Vascular anomalies: diagnosis of complicated anomalies and new medical treatment options. . Hematol. Oncol. Clin. N. Am. 33::455–70
     [Crossref] [Google Scholar]
  255. 255.
    Luisi F, Torre O, Harari S. 2016.. Thoracic involvement in generalised lymphatic anomaly (or lymphangiomatosis). . Eur. Respir. Rev. 25::170–77
     [Crossref] [Google Scholar]
  256. 256.
    Ozeki M, Aoki Y, Nozawa A, Yasue S, Endo S, et al. 2019.. Detection of NRAS mutation in cell-free DNA biological fluids from patients with kaposiform lymphangiomatosis. . Orphanet J. Rare Dis. 14::215
     [Crossref] [Google Scholar]
  257. 257.
    Croteau SE, Kozakewich HP, Perez-Atayde AR, Fishman SJ, Alomari AI, et al. 2014.. Kaposiform lymphangiomatosis: a distinct aggressive lymphatic anomaly. . J. Pediatr. 164::383–88
     [Crossref] [Google Scholar]
  258. 258.
    Rodriguez-Laguna L, Agra N, Ibañez K, Oliva-Molina G, Gordo G, et al. 2019.. Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly. . J. Exp. Med. 216::407–18
     [Crossref] [Google Scholar]
  259. 259.
    Barclay SF, Inman KW, Luks VL, McIntyre JB, Al-Ibraheemi A, et al. 2019.. A somatic activating NRAS variant associated with kaposiform lymphangiomatosis. . Genet. Med. 21::1517–24
     [Crossref] [Google Scholar]
  260. 260.
    Oishi S, Tsukiji N, Segawa T, Takano K, Hasuda N, Suzuki-Inoue K. 2024.. Abnormalities in C-type lectin-like receptor 2 in a patient with Gorham-Stout disease: the first case report. . Res. Pract. Thromb. Haemost. 8::102273
     [Crossref] [Google Scholar]
  261. 261.
    Sweet DT, Jimenez JM, Chang J, Hess PR, Mericko-Ishizuka P, et al. 2015.. Lymph flow regulates collecting lymphatic vessel maturation in vivo. . J. Clin. Investig. 125::2995–3007
     [Crossref] [Google Scholar]
/content/journals/10.1146/annurev-physiol-022724-105311
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The Lymphatic Vasculature in Lung Homeostasis and Disease
Annual Review of Physiology 87, 421 (2025); https://doi.org/10.1146/annurev-physiol-022724-105311
/content/journals/10.1146/annurev-physiol-022724-105311
/content/journals/10.1146/annurev-physiol-022724-105311
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