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Expression of inducible nitric oxide synthase and nitrotyrosine in borderline leprosy lesions
Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
Experimental Pathology Laboratory, Dept of Pathology, Instituto Nacional de la Nutrición Salvador Zubirán, Mexico City.
AHRI, Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
ALERT, All Africa Leprosy Relief and Training Hospital, Addis Ababa, Ethiopia.
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2001 (English)In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 145, no 5, 809-815 p.Article in journal (Refereed) Published
Abstract [en]

Background In the response to T-helper cell (Th1)-type cytokines and interactions with pathogens, high levels of nitric oxide (NO) are produced by activated macrophages expressing the inducible NO synthase (iNOS). The role and importance of reactive nitrogen intermediates (RNIs) such as NO and peroxynitrite in the host response to diseases caused by intracellular pathogens such as Mycobacterium leprae and M. tuberculosis is unclear.

Objectives The aim of this study was to investigate the presence of local production of NO and peroxynitrite in borderline leprosy by using antibodies against iNOS and the product of peroxynitrite, nitrotyrosine (NT).

Methods We detected the presence of iNOS and NT in skin biopsies from borderline leprosy patients, with and without reversal reaction (RR), by immunohistochemistry (n = 26).

Results In general, the granulomas from borderline leprosy lesions with and without RR showed high and specific expression of iNOS and NT. Moreover, strong immunoreactivity to iNOS and NT was observed in granulomas surrounding and infiltrating dermal nerves. The expression of iNOS and NT was also strong in keratinocytes, fibroblasts and endothelial cells in close relation to the granulomatous reaction. In contrast, normal human skin showed no expression of iNOS and NT in these cells.

Conclusions We conclude that iNOS and NT are expressed in granulomas from borderline leprosy patients with and without RR and propose that RNIs might be involved in the nerve damage following RR in leprosy.

Place, publisher, year, edition, pages
2001. Vol. 145, no 5, 809-815 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-26100DOI: 10.1046/j.1365-2133.2001.04491.xLocal ID: 10559OAI: diva2:246648
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-09-21Bibliographically approved
In thesis
1. Nitric oxide in tuberculosis and leprosy
Open this publication in new window or tab >>Nitric oxide in tuberculosis and leprosy
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a global disease that kills about two million people each year. Leprosy is caused by Mycobacterium leprae, and primarily affects the skin and peripheral nervous system. About 10-20% of leprosy patients suffer from reactions associated with acute inflammation that can lead to rapid and severe nerve damage. Most individuals infected with Mtb or M leprae do not develop clinical disease, which indicates that human hosts have effective defence mechanisms. In macrophages activated by cytokines such as IFN-γ, inducible nitric oxide synthase (iNOS) catalyses the production of nitric oxide (NO) from L-arginine. In an inflammatory environment, NO reacts with the superoxide radical (O2-) to yield peroxynitrite, an unstable metabolite that can rapidly nitrosylate tyrosine residues on proteins to form the stabile end product nitrotyrosine (NT). Many studies using experimental models have indicated that NO is important in host response to M leprae and Mtb, but this is controversial in human disease. Thus, our aim was to investigate the presence and the role of NO in the human mycobacterial infectious diseases TB and leprosy.

Levels of the NO metabolites nitrite and nitrate were initially increased in urine from patients with reactional leprosy but were normalised by treatment with prednisolone, and this was associated with clinical improvement. Immunohistochemistry revealed local production of NO in skin biopsies from patients with borderline leprosy and reversal reactions, which was detected as reactivity to iNOS and NT in macrophage-rich granulomas. Ultrastructural studies showed NT-positive aggregations of neurofilaments in dermal nerves from leprosy patients. Patients with active tuberculosis had increased urinary levels of NO metabolites, which were normalised after anti-TB treatment. Household contacts of patients with tuberculosis had increased levels of NO metabolites in plasma and serum. Immunohistochemical examination of biopsies from patients with TB indicated local, iN OS-mediated generation ofNO in macrophage-rich granulomas. In an experimental model of TB, local production of NO in the lungs was substantial in the acute phase of infection, and immunoelectron microscopy detected NT in phagosomes containing Mtb and on the surface of the bacteria. In an in vitro model, NO and peroxynitrite killed Mtb H37Ra and induced upregulation of several bacterial proteins. Peroxynitrite also mediated tyrosine nitration of albumin associated with the surface of Mtb. In a randomised, double-blind trial in Ethiopia, arginine supplementation in patients receiving conventional chemotherapy increased sputum conversion and reduced the prevalence of cough in HIV -negative, smear-positive patients with active TB.

In conclusion, these results demonstrate that iNOS-mediated production of NO occurs in human tuberculosis and leprosy; NO and peroxynitrite can kill Mtb and modify protein expression in the bacteria; and arginine leads to clinical improvement in TB patients.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2002. 106 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 749
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-26667 (URN)11233 (Local ID)91-7373-193-5 (ISBN)11233 (Archive number)11233 (OAI)
Public defence
2002-11-01, Berzeliussalen, Hälsouniversitetet, Linköping, 13:00 (Swedish)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-09-21Bibliographically approved

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