Hrev_master Veins and Lymphatics 2016; volume 5:5980 [page 2] [Veins and Lymphatics 2016; 5:5980] Inflammation and compression: the state of art Daniela Ligi, Lidia Croce, Ferdinando Mannello Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino (PU), Italy Chronic venous leg ulcer affects around 1- 2% of the adult population in the western world,1 with significant expenditures and high social and economic impact. The leading hemodynamic cause is represented by venous hypertension, affecting the venous macro- and micro-circulation, which is able to induce mor- phologic, functional and biochemical alter- ations in postcapillary venules and in the sur- rounding tissue microenvironment.2 In this regard, inflammatory processes by leukocytes and macrophages affect the venous endothelium, promoting a complex succession of events involving the activation of adhesion molecules, chemokines, cytokines, growth fac- tors, and proteases which cause endothelial dysfunction and dysregulation, compromising tissue integrity and finally lead to dermal dam- age and ulcer development.3 A critical aspect for treating venous leg ulcer is correcting the abnormal venous hemody- namics by compression therapy. In fact, com- pression therapy has been widely recognized as the cornerstone in the management of chronic venous insufficiency (CVI), clinical condition resulting from venous hypertension secondary to superficial or deep venous valvu- lar reflux and/or obstruction.4 Compression can be achieved using compression bandag- ing, compression pumps, or graduated com- pression stockings, which, by decreasing ambulatory venous hypertension in the area, counteract the chronic inflammation in the tis- sues and finally aide healing processes.5 It has been shown that ulcer dressings cre- ate and maintain a moist environment on the ulcer surface, promoting autolytic debride- ment, angiogenesis and a more rapid forma- tion of granulation tissue, favoring ker- atinocytes migration and finally accelerating healing of wounds, even if different wound dressings must be used according to the ulcer stages.6 In the recent revision of the Society for Vascular Surgery and American Venous Forum guidelines on management of venous leg ulcers performed by the International Union of Phlebology, it has been highlighted that …in a patient with a venous leg ulcer without arterial involvement or peripheral neuropathy, it is rec- ommend strong compression pressure (>40 mmHg resting pressure at the ankle) over low compression pressure to increase venous leg ulcer healing rate... suggesting Grade 1 and Level of Evidence B.7 Moreover, it has been provided evidence that strong (>40 mmHg) compression is more effective than low (<20 mmHg) compression in promoting ulcer heal- ing, including also that ...in a patient with a healed venous leg ulcer, the compression thera- py decreases the risk of ulcer recurrence... (Grade 2 and Level of Evidence B).7 Unfortunately, venous leg ulcer recurrence ranges between 30-70%, and other modalities in therapy along with the compression therapy are required. The goal for adjuvant products is to promote the shift from an inflammatory chronic wound to a reparative wound that will promote provisional extracellular matrix depo- sition and re-epithelialization. There are many products on the market that can be used as adjuvants to compression ther- apy; in this respect, it has been highlighted that …for long-standing or large venous leg ulcer, we recommend treatment with either pentoxifylline, micronized purified flavonoid fraction or sulodexide, all used in combination with compression therapy (Grade 1; Level of Evidence B);7 however, it must be recognized that there is a paucity of clinical trials that have evaluated the clinical effectiveness of specific products with clearly defined end points, and most importantly a healed venous leg ulcer with a low recurrence rate. Despite the treatment modalities are aimed at reduc- ing venous hypertension, some therapies, although widely used, only provide short-term improvement of the edema but do not provide long-term benefits.8 Chronic venous disease and CVI are charac- terized by an increase in ambulatory venous pressure but the different symptoms and signs clearly show that there is an inflammatory state secondary to venous hypertension, which leads to venous wall and valves injury.1 Several studies were performed to assess and demonstrate the efficacy of compression treatment in the management of chronic venous leg ulceration. An interesting random- ized controlled trial published in 2004, compar- ing compression treatment alone or in combi- nation with superficial venous surgery, demonstrated that 24-week healing rates were similar in the compression-surgery vs. com- pression alone groups, but 12-months ulcer recurrence rates were significantly reduced in the compression-surgery patients, suggesting, from a clinical point of view, that most patients with chronic venous ulceration will benefit from the combination of therapies added to simple surgery.9 It has also been demonstrated that significantly less legs in the compression- surgery treated patients developed perforator incompetence in comparison to the group treated with compression alone, offering more protection against developing new perforator incompetence.10 Although a plethora of studies have identi- fied up-regulation of various pro-inflammatory cytokines in fluid collected from venous leg ulcers,11 and even if the compression therapy results in healing of most venous leg ulcers, the biomolecular mechanism(s) responsible for this effect is not well understood. In this respect, an interesting study per- formed on biopsies from ulcerated tissue from non-healing chronic venous insufficiency affected patients treated with high-compres- sion therapy revealed that compression thera- py (with 3-layer or 4-layer compression band- age system for 4 weeks) resulted in healing coupled with reduced pro-inflammatory cytokines [e.g., interleukin (IL)-1�, interferon- g, granulocyte-macrophage colony-stimulating factor] and higher levels of the anti-inflamma- tory cytokine IL-1RA.12 Similarly, it has been previously reported that wound healing of venous ulcers treated with compression thera- py correlated with decreasing serum levels of tumor necrosis factor-a and vascular endothe- lial growth factor13 and increasing exudate lev- els of transforming growth factor-b�1.14 Moreover, it is well known that an alteration of the proteolytic and anti-proteolytic balance is significantly implicated in chronic wound initiation and progression. In this regard, it has been investigated in venous leg ulcer tis- sues the effect of sustained limb compression of 30 mmHg (or greater) for 4 weeks on ulcer healing rates, demonstrating that stromelysin matrix metalloproteinase (MMP)-3, collage- nase MMP-8 and gelatinase MMP-9 were sig- nificantly reduced after the compression treat- ment, and suggesting that a down-regulation of proteinases in ulcer tissue microenviron- ment by compression may represent a possible mechanism (in conjunction to the decrease of inflammation) to counteract the progression of CVI and improve venous ulcer healing.15 More recently, it has been reported that venous ulcers treated with a multi-layer bandaging system showed decreased plasma levels of MMP-9, TIMP-1, and MMP-2/TIMP-2 ratio in healed wounds.16 Finally, a recent randomized placebo-con- trolled trial assessed the efficacy of elastic compression stocking to prevent post-throm- Correspondence: Ferdinando Mannello, Department of Biomolecular Sciences, University of Urbino Carlo Bo, via Aurelio Saffi 2, 61029 Urbino (PU), Italy. E-mail: ferdinando.mannello@uniurb.it This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright D. Ligi et al., 2016 Licensee PAGEPress, Italy Veins and Lymphatics 2016; 5:5980 doi:10.4081/vl.2016.5980 No n c om me rci al us e o nly Conference presentation [Veins and Lymphatics 2016; 5:5980] [page 3] botic syndrome; although the study showed several bias weakening the entire protocol, their results suggested that elastic compres- sion did not prevent post-thrombotic syn- drome, not supporting routine wearing of elas- tic compression stocking after deep vein thrombosis.17 Noteworthy is the scarce pres- ence of biomolecular evidence of elastic com- pression efficacy on swelling and inflamma- tion, suggesting that further studies are need- ed to clarify the mechanisms of stocking effi- cacy in down-regulation of hemodynamic and inflammatory processes implicated in CVI and deep venous thrombosis. For what concerns the future perspectives, on the basis of previous studies performed in animal models18 and human cell lines,19,20 it is noteworthy that glycosaminoglycans in con- junction to compression therapy may improve ulcer healing,21 due to their effectiveness in down-regulating the release of cytokines, chemokines and leukocyte colony stimulating factors from human macrophages and in mod- ulating the inflammatory pathways. The effects of glycosaminoglycans could actually enhance the effects of compression therapy on inflammation mediators. References 1. Raffetto JD, Mannello F. Patho-physiology of chronic venous disease. Int Angiol 2014;33:212-21. 2. Raffetto JD. Which dressings reduce inflammation and improve venous leg ulcer healing. Phlebology 2014;29:157-64. 3. Mannello F, Raffetto JD. Matrix metallo- proteinase activity and glycosaminogly- cans in chronic venous disease: the link- age among cell biology, pathology, and translational research. Am J Transl Res 2011;3:149-58. 4. Kolluri R. Management of venous ulcers. Tech Vasc Interv Radiol 2014;17:132-8. 5. Carr SC. Diagnosis and management of venous ulcers. Perspect vasc Surg Endovasc Ther 2008;20:82-5. 6. Mosti G. Wound care in venous ulcers. Phlebology 2013;28:79-85. 7. Mosti G, De Maeseneer M, Cavezzi A, et al. Society for Vascular Surgery and American Venous Forum Guidelines on the manage- ment of venous leg ulcers: the point of view of the International Union of Phlebology. Int Angiol 2015;34:202-18. 8. Raffetto JD, Eberhardt RT, Dean SM, et al. Pharmacologic treatment to improve venous leg ulcers healing. J Vasc Surg Venous Lymphatic Disorder 2015 [Epub ahead of print]. 9. Barwell JR, Davies CE, Deacon J, et al. Comparison of surgery and compression with compression alone in chronic venous ulceration (ESCHAR study): randomized controlled trial. Lancet 2004;363:1854-9. 10. Gohel MS, Barwell JR, Wakely C, et al. The influence of superficial venous surgery and compression on incompetent perfora- tors in chronic venous leg ulceration. Eur J Vasc Endovasc Surg 2005;29:78-82. 11. Mannello F, Ligi D, Canale M, Raffetto JD. Omics profiles in chronic venous ulcer wound fluid: innovative applications for translational medicine. Exp Rev Mol Diagn 2014;14:737-62. 12. Beidler SK, Douillet CD, Berndt DF, et al. Inflammatory cytokine levels in chronic venous insufficiency ulcer tissue before and after compression therapy. J Vasc Surg 2009;49:1013-20. 13. Murphy MA, Joyce WP, Condron C, Bouchier-Hayes D. A reduction in serum cytokine levels parallels healing of venous ulcers in patients undergoing compres- sion therapy. Eur J Vasc Endovasc Surg 2002;23:349-52. 14. Gohel MS, Windhaber RA, Tarlton JF, et al. The relationship between cytokine con- centrations and wound healing in chronic venous ulceration. J Vasc Surg 2008;48:1272-7. 15. Beidler SK, Douillet CD, Berndt DF, et al. Multiplexed analyses of matrixmetallopro- teinases in leg ulcer tissue of patients with chronic venous insufficiency before and after compression therapy. Wound Repair Regen 2008;16:642-8. 16. Caimi G, Ferrara F, Montana M, et al. Behaviour of the plasma concentration of gelatinases and their tissue inhibitors in subjects with venous leg ulcers. Clin Hemorheol Microcirc. 2015;60:309-16. 17. Kahn SR, Shapiro S, Wells PS, et al. Compression stockings to prevent post- thrombotic syndrome: a randomized place- bo-controlled trial. Lancet 2014;383:880-8. 18. Tong M, Tuk B, Hekking IM, et al. Heparan sulphate glycosaminoglycan mimetic improves pressure ulcer healing in a rat model of cutaneous ischemia-reperfusion injury. Wound Repair Regen 2011;19:505-14. 19. Mannello F, Medda V, Ligi D, Raffetto JD. Glycosaminoglycan sulodexide inhibition of MMP-9 gelatinase secretion and activi- ty: possible pharmacological role against collagen degradation in vascular chronic diseases. Curr Vasc Pharmacol 2013;11: 354-65. 20. Mannello F, Ligi D, Canale M, Raffetto JD. Sulodexide down-regulates the release of cytokines, chemokines and leukocyte colony stimulating factors from human macrophages: role of glycosaminoglycans in inflammatory pathways of chronic venous disease. Curr Vasc Pharmacol 2014;12:173-85. 21. Mannello F, Ligi D, Raffetto JD. Glycosa - minoglycan sulodexide modulates inflam- matory pathways in chronic venous dis- ease. Int Angiol 2015;33:236-42. No n c om me rci al us e o nly