Tuberculoid leprosy: An in vivo microvascular evaluation of cutaneous lesions

Autoři: Livia Pino aff001;  Maria das Graças Coelho de Souza aff001;  Omar Lupi aff002;  Eliete Bouskela aff001
Působiště autorů: Laboratório de Pesquisas Clínicas e Experimentais em Biologia Vascular, Centro Biomédico, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, Rio de Janeiro, Brazil aff001;  Departamento de Dermatologia, Universidade Federal do Estado do Rio de Janeiro (UniRio), Rio de Janeiro, Rio de Janeiro, Brazil aff002
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0227654


Tuberculoid leprosy (TT) is characterized by cutaneous lesions called plaques. Although microvascular ultrastructure of TT patients’ skin is well-documented, little is known about functional aspects of their microcirculation. We aimed, for the first time, to evaluate, in vivo, the microcirculation of TT cutaneous lesions. Seven TT patients, males, under treatment were included in the study. The spectral analysis of frequency components of flowmotion (endothelial, sympathetic, myogenic, cardiac and respiratory) was performed using laser Doppler flowmetry (LDF). Endothelial dependent and independent vasodilatations were assessed by LDF associated to acetylcholine (ACh) and sodium nitroprusside (SNP) iontophoresis, respectively. Vessel density (VD), perfused vessel density (PVD), proportion of perfused vessels (PPV%), microvascular flow index (MFI) and flow heterogeneity index (FHI), reflecting tissue perfusion and oxygenation, were evaluated through sidestream dark field (SDF) imaging. All microvascular analysis were performed in TT lesions and in healthy skin in the contralateral limb of the same patient, used as control skin. VD, PVD and PPV% and MFI were significantly lower in the cutaneous lesion compared to contralateral healthy skin. The contribution of different frequency components of flowmotion, endothelial dependent and independent vasodilatations and FHI were not statistically different between control skin and cutaneous lesion. Our results suggest that TT cutaneous lesions have a significant impairment of tissue perfusion, which may aggravate peripheral nerve degeneration caused by Mycobacterium leprae infection.

Klíčová slova:

Blood flow – Capillaries – Leprosy – Lesions – Microcirculation – Oxygen – Iontophoresis – Mycobacterium leprae


1. Walker SL, Lockwood DNJ. Leprosy. Clin Dermatol. 2007; 25:165–172. doi: 10.1016/j.clindermatol.2006.05.012 17350495

2. Britton WJ, Lockwood DN. Leprosy. Lancet. 2004; 363:1209–1219. doi: 10.1016/S0140-6736(04)15952-7 15081655

3. Agrawal A, Pandit L, Dalal M, Shetty JP. Neurological manifestations of Hansen’s disease and their management. Clin Neurol Neurosurg. 2005; 107:445–454. doi: 10.1016/j.clineuro.2005.03.007 16202816

4. Nath I, Saini C, Valluri VL. Immunology of leprosy and diagnostic challenges. Clin Dermatol. 2015; 33:90–98. doi: 10.1016/j.clindermatol.2014.07.005 25432814

5. Ridley DS, Jopling WH. Classification of leprosy according to immunity. A five-group system. Int J Lepr Other Mycobact Dis. 1966; 34:255–273. 5950347

6. Yajima M, Murata J, Yamada N, Asano G. Ultrastructural observations of small blood vessels in leprosy patients. Nihon Rai Gakkai Zasshi. 1991; 60:121–127. doi: 10.5025/hansen1977.60.121 1843224

7. Kumar V, Narayanan RB, Malaviya GN. An ultrastructural study of blood vessels in peripheral nerves of leprosy patients: blood vessels in peripheral nerves. Nihon Rai Gakkai Zasshi. 1989; 58:179–184. doi: 10.5025/hansen1977.58.179 2642166

8. Cavender DE, Edelbaum D, Ziff M. Endothelial Cell Activation Induced by Tumor Necrosis Factor and Lymphotoxin. Am J Pathol 1989; 134:551–556. 2466402

9. Kraemer-Aguiar LG, Laflor CM, Bouskela E. Skin microcirculatory dysfunction is already present in normoglycemic subjects with metabolic syndrome. Metabolism. 2008; 57:1740–1746. doi: 10.1016/j.metabol.2008.07.034 19013299

10. Jonk AM, Houben AJ, Schaper NC, de Leeuw PW, Serné EH, Smulders YM, et al. Meal-related increases in microvascular vasomotion are impaired in obese individuals: a potential mechanism in the pathogenesis of obesity-related insulin resistance. Diabetes Care. 2011;34: S342–S348. doi: 10.2337/dc11-s240 21525480

11. Bouskela E, Grampp W. Spontaneous vasomotion in hamster cheek pouch arterioles in varying experimental conditions. Am J Physiol. 1992; 262:H478–H485. doi: 10.1152/ajpheart.1992.262.2.H478 1539706

12. Rossi M, Carpi A, Galetta F, Franzoni F, Santoro G. The investigation of skin blood flowmotion: a new approach to study the microcirculatory impairment in vascular diseases? Biomed Pharmacother. 2006; 60:437–442. doi: 10.1016/j.biopha.2006.07.012 16935461

13. Bertuglia S, Coluantoni A, Coppini G, Intaglietta M. Hypoxia or hyperoxia–induced changes in arteriolar vasomotion in skeletal muscle microcirculation. Am J Physiol. 1991; 260: H362–H372. doi: 10.1152/ajpheart.1991.260.2.H362 1996682

14. Turner J, Belch JJ, Khan F. Current concepts in assessment of microvascular endothelial function using laser Doppler imaging and iontophoresis. Trends Cardiovasc Med. 2008; 18:109–116. doi: 10.1016/j.tcm.2008.02.001 18555183

15. Tesselaar E, Sjöberg F. Transdermal iontophoresis as an in-vivo technique for studying microvascular physiology. Microvasc Res. 2011; 81:88–96. doi: 10.1016/j.mvr.2010.11.002 21070791

16. De Backer D, Hollenberg S, Boerma C, Goedhart P, Büchele G, Ospina-Tascon G, et al. How to evaluate the microcirculation: report of a round table conference. Crit Care. 2007; 11: R101. doi: 10.1186/cc6118 17845716

17. Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through VI. Arch Dermatol. 1988;124: 869–871. doi: 10.1001/archderm.124.6.869 3377516

18. Buss C, Kraemer-Aguiar LG, Maranhão PA, Marinho C, de Souza MD, Wiernsperger N, et al. Novel findings in the cephalic phase of digestion: a role for microcirculation? Physiol Behav. 2012; 105:1082–1087. doi: 10.1016/j.physbeh.2011.12.004 22197630

19. Stefanovska A, Bracic M, Kvernmo HD. Wavelet analysis of oscillations in the peripheral blood circulation measured by laser Doppler technique. IEEE Trans Biomed Eng. 1999; 46:1230–1239. doi: 10.1109/10.790500 10513128

20. Serné EH, IJzerman RG, Gans RO, Nijveldt R, De Vries G, Evertz R, et al. Direct evidence for insulin-induced capillary recruitment in skin of healthy subjects during physiological hyperinsulinemia. Diabetes. 2002; 51:1515–1522. doi: 10.2337/diabetes.51.5.1515 11978650

21. Kvernmo HD, Stefanovska A, Bracic M, Kirkebøen KA, Kvernebo K. Spectral analysis of the laser Doppler perfusion signal in human skin before and after exercise. Microvasc Res. 1998; 56:173–182. doi: 10.1006/mvre.1998.2108 9828155

22. Treu C, de Souza MDGC, Lupi O, Sicuro FL, Maranhão PA, Kraemer-Aguiar LG, et al. Structural and functional changes in the microcirculation of lepromatous leprosy patients—Observation using orthogonal polarization spectral imaging and laser Doppler flowmetry iontophoresis. Plos One. 2017;12:e0175743. doi: 10.1371/journal.pone.0175743 28419120

23. Massey MJ, Shapiro NI. A guide to human in vivo microcirculatory flow image analysis. Crit Care. 2016; 20:35. doi: 10.1186/s13054-016-1213-9 26861691

24. Trzeciak S, Dellinger RP, Parrillo JE, Guglielmi M, Bajaj J, Abate NL, et al. Microcirculatory Alterations in Resuscitation and Shock Investigators. Early microcirculatory perfusion derangements in patients with severe sepsis and septic shock: relationship to hemodynamics, oxygen transport, and survival. Ann Emerg Med. 2007; 49:88–98.

25. Humer MF, Phang PT, Friesen BP, Allard MF, Goddard CM, Walley KR, et al. Heterogeneity of gut capillary transit times and impaired gut oxygen extraction in endotoxemic pigs. J Appl Physiol. 1996; 81:895–904. doi: 10.1152/jappl.1996.81.2.895 8872661

26. Farquhar I, Martin CM, Lam C, Potter R, Ellis CG, Sibbald WJ. Decreased capillary density in vivo in bowel mucosa of rats with normotensive sepsis. J Surg Res. 1996; 61:190–196. doi: 10.1006/jsre.1996.0103 8769965

27. Ellis CG, Bateman RM, Sharpe MD Sibbald WJ, Gill R. Effect of a maldistribution of microvascular blood flow on capillary O2 extraction in sepsis. Am J Physiol. 2002; 282:H156–H164.

28. De Backer D, Ospina-Tascon G, Salgado D, Favory R, Creteur J, Vincent JL. Monitoring the microcirculation in the critically ill patient: current methods and future approaches. Intensive Care Med. 2010;36:1813–1825. doi: 10.1007/s00134-010-2005-3 20689916

29. Tafner PFDA, Chen FK, Rabello R Filho, Corrêa TD, Chaves RCF, Serpa A Neto. Recent advances in bedside microcirculation assessment in critically ill patients. Rev Bras Ter Intensiva. 2017; 29:238–247. doi: 10.5935/0103-507X.20170033 28977264

30. Tyml K, Yu J, McCormack DG. Capillary and arteriolar responses to local vasodilators are impaired in a rat model of sepsis. J Appl Physiol (1985). 1998; 84:837–844.

31. Massone C, Belachew WA, Schettini A. Histopathology of the lepromatous skin biopsy. Clin Dermatol. 2015; 33:38–45. doi: 10.1016/j.clindermatol.2014.10.003 25432809

32. Naafs B, van Hees CL. Leprosy type 1 reaction (formerly reversal reaction). Clin Dermatol. 2016; 34:37–50. doi: 10.1016/j.clindermatol.2015.10.006 26773622

33. Wheate HW. Acute edema in leprosy. Int J Lepr. 1962; 30:388–394. 14000220

34. Turkel SB, Van Hale HM, Rea TH. Ultrastructure of the dermal microvasculature in leprosy. Int J Lepr Other Mycobact Dis. 1982; 50:164–171. 6889577

35. Scollard DM, McCormick G, Allen JL. Localization of M. leprae to endothelial cells of epineural and perineurial blood vessels and lymphatics. Am J Pathol. 1999; 154:1611–1620.

36. Scollard DM. Association of Mycobacterium leprae with human endothelial cells in vitro. Lab Invest. 2000; 80:663–669. doi: 10.1038/labinvest.3780069 10830776

37. Wilder-Smith A, Wilder-Smith E. Electrophysiological evaluation of peripheral autonomic function in leprosy patients, leprosy contacts and controls. Int J Lepr Other Mycobact Dis. 1996; 64:433–440. 9030110

38. Illarramendi X, Bührer-Sékula S, Sales AM, Bakker M I, Oliveira A, Nery JAC et al. High prevalence of vasomotor reflex impairment in newly diagnosed leprosy patients. Eur J Clin Invest. 2005; 35: 658–665. doi: 10.1111/j.1365-2362.2005.01554.x 16178886

39. Karanth SS, Springall DR, Lucas S, Levy D, Ashby P, Levene MM, et al. Changes in nerves and neuropeptides in skin from 100 leprosy patients investigated by immunocytochemistry. J Pathol. 1989; 157:15–26. doi: 10.1002/path.1711570104 2466111

40. Cracowski JL, Minson CT, Salvat-Melis M, Halliwill JR. Methodological issues in the assessment of skin microvascular endothelial function in humans. Trends Pharmacol Sci. 2006; 27:503–508. doi: 10.1016/ 16876881

41. De Jongh RT, Serne EH, IJzerman RG, Stehouwer CD. Microvascular function: a potential link between salt sensitivity, insulin resistance and hypertension. J Hypertens. 2007; 25:1887–1893. doi: 10.1097/HJH.0b013e32825e1db7 17762653

42. Struijker-Boudier HA, Rosei AE, Bruneval P, Camici PG, Christ F, Henrion D, et al. Evaluation of the microcirculation in hypertension and cardiovascular disease. Eur Heart J. 2007; 28:2834–2840. doi: 10.1093/eurheartj/ehm448 17942581

43. Quattrini C, Harris ND, Malik RA, Tesfaye S. Impaired skin microvascular reactivity in painful diabetic neuropathy. Diabetes Care. 2007; 30:655–659. doi: 10.2337/dc06-2154 17327336

44. De Jongh RT, Serne EH, IJzerman RG, Jorstad HT, Stehouwer CD. Impaired local microvascular vasodilatory effects of insulin and reduced skin microvascular vasomotion in obese women. Microvasc Res. 2008; 75:256–262. doi: 10.1016/j.mvr.2007.08.001 17920639

45. Li L, Mac-Mary S, Marsaut D Sainthillier JM, Nouveau S, Gharbi T, et al. Age-related changes in skin topography and microcirculation. Arch Dermatol Res. 2006; 297:412–416. doi: 10.1007/s00403-005-0628-y 16328340

46. Li L, Mac-Mary S, Sainthillier JM, Nouveau S, de Lacharriere O, Humbert P. Age-related changes of the cutaneous microcirculation in vivo. Gerontology. 2006; 52:142–153. doi: 10.1159/000091823 16645294

47. Monfrecola G, Riccio G, Savarese C, Posteraro G, Procaccini EM. The acute effect of smoking on cutaneous microcirculation blood flow in habitual smokers and nonsmokers. Dermatology. 1998; 197:115–118. doi: 10.1159/000017980 9732157

48. Pellaton C, Kubli S, Feihl F, Waeber B. Blunted vasodilatory responses in the cutaneous microcirculation of cigarette smokers. Am Heart J. 2002; 144:269–274. doi: 10.1067/mhj.2002.123842 12177644

49. IJzerman RG, Serne EH, van Weissenbruch MM, De Jongh RT, Stehouwer CD. Cigarette smoking is associated with an acute impairment of microvascular function in humans. Clin Sci (Lond). 2003; 104:247–252.

50. Edvinsson ML, Andersson SE, Xu CB, Edvinsson L. Cigarette smoking leads to reduced relaxant responses of the cutaneous microcirculation. Vasc Health Risk Manag. 2008; 4:699–704. doi: 10.2147/vhrm.s2285 18827920

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