Chronic lower limb wounds evoke systemic response of the lymphatic (immune) system

ABSTRACT

Wound healing should not be considered as a process limited only to the damaged tissues. It is always accompanied by an intensive local immune response and in advanced stages, the systemic lymphatic (immune) structure. In this review we present evidence from our own studies as well as pertinent literature on the role of skin and subcutaneous tissue lymphatics at the wound site and of transport of antigens along with collecting afferent lymphatics to the lymph nodes. We also speculate the role of lymph nodes in raising cohorts of bacterial and own tissue antigen-specific lymphocytes and their participation in healing and not infrequently evoking uncontrolled chronic immune reaction causing a delay of healing. It is also speculated as to why there is a rapid response of lymph node cells to microbial antigens and tolerance to damaged-tissue-derived antigens occurs

KEY WORDS

Healing - immunity - wound

• 1 Olszewski WL, Engeset A. Immune proteins, enzymes and electrolytes in human peripheral lymph. Lymphology 1978;11:156-64.
• 2 Olszewski WL, Loe K, Engeset A. Immune proteins and other biochemical constituents of peripheral lymph in patients with malignancy and postirradiation lymphedema. Lymphology. 1978;11:174-80.
• 3 Olszewski WL, Pazdur J, Kubasiewicz E, Zaleska M, Cooke CJ, Miller NE. Lymph draining from foot joints in rheumatoid arthritis provides insight into local cytokine and chemokine production and transport to lymph nodes. Arthritis Rheum 2001;44:541-9.
• 4 Olszewski WL. Pathophysiological aspects of lymphedema of human limbs: I. Lymph protein composition. Lymphat Res Biol 2003;1:235-43.
• 5 Olszewski WL, Jamal S, Manokaran G, Lukomska B, Kubicka U. Skin changes in filarial and non-filarial lymphoedema of the lower extremities. Trop Med Parasitol 1993;44:40-4.
• 6 Olszewski WL, Ambujam PJ, Zaleska M, Cakala M. Where do lymph and tissue fluid accumulate in lymphedema of lower limbs caused by obliteration of lymphatic collectors. Lymphology 2009:42:105-111.
• 7 Costello EK, Lauber Ch, Hamady M, Fierer N, Gordon JI, Knight R. Bacterial community variation in human body habitats across space and time. Science 2009;326:1694-7.
• 8 Gao Z, Tseng CH, Pei Z, Blaser MJ. Molecular analysis of human forearm superficialskin bacterial biota. Proc Natl Acad Sci U S A. 2007;104:2927-32.
• 9 Kloos WE, Musselwhite MS. Distribution and Persistence of Staphylococcus and Micrococcus Species and Other Aerobic Bacteria on Human Skin. Appl Microbiol 1975;30:381-5.
• 10 Szczesny G, Interewicz B, Swoboda-Kopec E, Olszewski WL, Gorecki A, Wasilewski P. Bacteriology of callus of closed fractures of tibia and femur. J Trauma 2008;65:837-42.
• 11 Andziak P, Olszewski WL, Moscicka-Wesolowska M, Interewicz B, Swoboda E, Stelmach E. Skin own bacteria may aggravate inflammatory and occlusive changes in atherosclerotic arteries of lower limbs. Int Angiol 2012.
• 12 Olszewski WL, Jamal S, Manokaran G, Pani S, Kumaraswami V, Kubicka U, et al. Bacteriologic studies of skin, tissue fluid, lymph, and lymph nodes in patients with filarial lymphedema. Am J Trop Med Hyg 1997;57:7-15.
• 13 Olszewski WL, Grzelak I, Ziolkowska A, Engetset A. Immune cell traffic from blood through the normal human skin to lymphatics. Clin Dermatol 1995;13:473-83.
• 14 Szczesny G, Veihelmann A, Nolte D, Messmer K. Changes in the local blood and lymph microcirculation in response to direct mechanical trauma applied to leg: In vivo study in an animal model. J Trauma 2001;51:508-17.
• 15 Ji RC. Lymphatic endothelial cells, lymphangiogenesis, and extracellular matrix. Lymphat Res Biol 2006;4:83-100.
• 16 Hong YK, Lange-Asschenfeldt B, Velasco P, Hirakawa S, Kunstfeld R, Brown LF, et al. VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the alpha1 beta1 and alpha2 beta1 integrins. FASEB J 2004;18:1111- 3.
• 17 Paavonen K, Puolakkainen P, Jussila L, Jahkola T, Alitalo K Vascular endothelial growth factor receptor-3 in lymphangiogenesis in wound healing. Am J Pathol 2000;15:1499-504.
• 18 Ji RC, Miura M, Qu P, Kato S. Expression of VEGFR-3 and 5′-nase in regenerating lymphatic vessels of the cutaneous wound healing. Microsc Res Tech 2004;64:279-86.
• 19 Smaropoulos EC, Papazoglou LG, Patsikas MN, Vretou E, Petropoulos AS. Lymphatic regeneration following hind limb replantation: An experimental study in the dog. Eur J Pediatr Surg 2005;15:337-42.
• 20 Maruyama K, Asai J, Ii M, Thorne T, Losordo DW, D′Amore PA. Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing. Am J Pathol 2007;170:1178-91.
• 21 Nogami M, Hoshi T, Arai T, Toukairin Y, Takama M, Takahashi I. Morphology of lymphatic regeneration in rat incision wound healing in comparison with vascular regeneration. Leg Med (Tokyo) 2009;11:213-8.
• 22 Avraham T, Daluvoy S, Zampell J, Yan A, Haviv YS, Rockson SG, et al. Blockade of Transforming Growth Factor-1 Accelerates Lymphatic Regeneration during Wound Repair. Am J Pathol 2010;177:3202-14.
• 23 Zampell, JC, Yan, Avraham,T Daluvoy S, Weitman ES. Mehrara BJ. HIF-1á coordinates lymphangiogenesis during wound healing and in response to inflammation. FASEB J 2012;26:1027-39.
• 24 Szczesny G, Olszewski WL. The pathomechanism of posttraumatic edema of lower limbs: I. The effect of extravasated blood, bone marrow cells, and bacterial colonization on tissues, lymphatics, and lymph nodes. J Trauma 2002;52:315-22.
• 25 Szczesny G, Olszewski WL, Zaleska M. Limb lymph node response to bone fracture.Lymphat Res Biol 2004;2:155-64.
• 26 Szczesny G, Olszewski WL. The pathomechanism of posttraumatic edema of the lower limbs: II-Changes in the lymphatic system. J Trauma 2003;55:350-4.