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Expression of inducible nitric oxide synthase and nitrotyrosineduring the evolution of experimental pulmonary tuberculosis
Experimental Pathology Laboratory. Department of Pathology, Instituto Nacional De Ciencias Médicas y Nutrición “Salvador Zubirán”, Mexico city, Mexico.
Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
Experimental Pathology Laboratory. Department of Pathology, Instituto Nacional De Ciencias Médicas y Nutrición “Salvador Zubirán”, Mexico city, Mexico.
Department of Immunology, Escuela Nacional de Ciencias Biológicas. Instituto Politecnico Nacional, México city, Mexico.
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2001 (English)In: Experimental and Toxicological Pathology, ISSN 0940-2993, E-ISSN 1618-1433, Vol. 53, no 4, 257-265 p.Article in journal (Refereed) Published
Abstract [en]

Nitric oxide (NO) is a relevant antimycobacterial factor in mouse macrophages. NO is a product of inducible nitric oxide synthase (iNOS). NO toxicity is greatly enhanced by reacting with superoxide to form peroxynitrite that reacts with many biological molecules. Tyrosine is one of the molecules with which NO reacts and the product is nitrotyrosine (NT). The production of peroxynitrite and the nitrosylation of proteins might play a role in bacterial killing and also in mediating host injury. In this study, we used a well-characterized mouse model of pulmonary tuberculosis to examine the local kinetics of expression and cellular distribution of iNOS and NT at the cellular and subcellular level. The histopathological study showed two phases of the disease: early and late. The early phase was characterized by mononuclear inflammation and granuloma formation. During this phase, high percentages of activated macrophages were observed that were immunostained for iNOS and NT. Immuno-electronmicroscopy showed NT immunoreactivity in lysosomes and mycobacterial wall and cytoplasm. The concentration of iNOS mRNA and NO metabolites were also elevated. The late phase was characterized by progressive pneumonia with focal necrosis and a decrease of iNOS mRNA and NO metabolites. The strongest NT immunostained areas were the necrotic tissue. Macrophages became foamy cells with scarce iNOS immunostaining but strong NT immunoreactivity. At the ultrastructural level, these cells showed NT immunolabeling in cytoskeleton, mitochondria, lysosomes and cell membrane. NT was also located in bronchial epithelial cell mitochondria, in cell membranes and cytoplasm of endothelial cells and in actin bundles within smooth muscle cells. These results suggest an important role of NO in mycobacterial killing, particularly during the early phase of the infection. They also suggest an important participation by NO in tissue damage during the late phase of the disease.

Place, publisher, year, edition, pages
2001. Vol. 53, no 4, 257-265 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-26099DOI: 10.1078/0940-2993-00182Local ID: 10558OAI: oai:DiVA.org:liu-26099DiVA: diva2:246647
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.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 749
National Category
Medical and Health Sciences
Identifiers
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)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-09-21Bibliographically approved

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