© 2003 American Thoracic Society
Nitric oxide and tuberculosis infectionTo the Editor:The article by Choi and colleagues (1) attempted to elucidate a controversial issue regarding the human expression of nitric oxide synthase (NOS) and the potential role of nitric oxide (NO) against Mycobacterium tuberculosis infection. Choi and colleagues (1) described immunoreactivity for NOS and nitrotyrosine in lung tissue of tuberculosis patients. Our group is performing a similar study including induced NOS and nitrotyrosine immunostaining in lung biopsy samples from patients with newly diagnosed tuberculosis and normal lung tissue samples as controls. We found a distinct pattern of patchy distribution of macrophage immunostaining within the granulomas. We also found a strong immunoreactivity in alveolar macrophages and surrounding bronchial epithelial cells. Choi and colleagues did not mention this "patchy" pattern of distribution of macrophage NOS immunoreactivity. The type of lung tissue samples used by Choi and colleagues could explain an absence of this type of pattern findings. They obtained lung samples from eight patients (seven cases of multidrug-resistant tuberculosis, and one case of "recalcitrant drug susceptible tuberculosis") with very chronic forms of pulmonary tuberculosis. The pathologic features of three distinctive layers of pulmonary granulomas included a fibrous tissue layer, also supporting our impression of the long-term chronicity of those lesions. We feel there is a significant sample bias in Choi and colleagues' study, and the authors cannot extrapolate the type of NOS immunostaining of their study with other forms of tuberculosis infections such as new onset tuberculosis or new latent tuberculosis infection. Interestingly, the NOS immunoreactivity of bronchial epithelial cells, and reports of M. tuberculosis DNA in non-macrophage cells by in situ PCR in "normal lungs" in autopsy specimens of subjects from endemic areas (2), may suggest an additional role of NOS in the innate containment of M. tuberculosis by nonprofessional phagocytes. On the contrary, we were unable to reproduce the results from Wang and colleagues (3), and we found no significant differences in exhaled NO in newly diagnosed tuberculosis patients compared with normal subjects, using carefully controlled sampling methods (4). These observations may suggest a more complex compartmental and perhaps time-dependant relationship of human expression of NOS within the newly forming granulomatous tuberculosis lesions and surrounding tissues. In our estimation, the role of NOS in new onset tuberculosis infection is still unclear, and more research needs to be done to elucidate the actual role of NOS in human innate and immune defense against M. tuberculosis infection.
a University of Southern California Los Angeles, California REFERENCES
From the Authors:Drs. Escalante and Cagle noted that they found a "distinct pattern of patchy distribution of macrophage staining within the granulomas" of their patients with newly diagnosed tuberculosis. They also noted strong immunoreactivity of inducible nitric oxide synthase (iNOS) (and presumably nitrotyrosine) in alveolar macrophages and surrounding bronchial epithelial cells. We are uncertain as to their meaning of the "distinct pattern of patchy distribution" of iNOS (and possibly nitrotyrosine) expression. Do they mean that in the granulomas (1) there were patchy areas of macrophages that stained, or (2) that some macrophages were stained and others were not in any one particular area, resulting in another form of patchy areas of staining? In our tuberculous lung tissues (1), the vast majority of the macrophages were stained, but obviously, there were patchy areas of macrophages, i.e., some areas contained more macrophages than others whereas other areas did not contain any macrophages. To the best of our knowledge, we did not "extrapolate the type of NOS immunostaining of [our] study with other forms of tuberculosis infections such as new onset tuberculosis or new latent tuberculosis infection" so we do not understand the statement that there was significant bias in our study. Although we agree that it would be interesting to distinguish immunohistochemistry findings in persons with new onset tuberculosis versus those with chronic tuberculosis, the definition of the former may be quite different from newly diagnosed tuberculosis, in which the infection may be already well established. The lung tissues used in our study were surgically resected lungs (i.e., lobectomy or even pneumonectomy), rather than a biopsy, so the samples are large and quite representative of the diseased lungs. As noted in our paper, this was purely a descriptive study, but we agree with Drs. Escalante and Cagle that more elucidation is needed on the role of nitric oxide in human tuberculosis.
National Jewish Medical and Research Center Denver, Colorado REFERENCES
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