Expression of inducible nitric oxide synthase in rat pulmonary Cryptococcus neoformans granulomas

David Goldman, Youngsoo Cho, Meng Liang Zhao, Arturo Casadevall, Sunhee C. Lee

Research output: Contribution to journalArticle

Abstract

Rats, like humans, have extremely effective immune mechanisms for controlling pulmonary Cryptococcus neoformans infection. The mechanism(s) responsible for efficient immunity in rat experimental infection is unknown. Recently, induction of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) have been implicated as an important microbicidal mechanism by which activated macrophages effect cytotoxicity against microbes. In this report, we investigated the expression of iNOS in rat pulmonary cryptococcosis. Localization and regulation of NO production was studied by immunohistochemistry for iNOS in conjunction with immunohistochemistry for cell markers, cytokines, and cryptococcal capsular polysaccharide. iNOS immunoreactivity was detected in macrophages, neutrophils, vascular endothelium, and respiratory epithelium. Double-immunolabeling studies revealed that the most prominent iNOS immunoreactivity was localized to epithelioid macrophages (CD11b/c+) within granulomas; CD4+ and CD8+ T cells were numerous around granulomas but did not express iNOS. iNOS immunoreactivity was detected in a selective population of epithelioid macrophages within some granulomas but not others. iNOS- granulomas were identical to iNOS+ granulomas with respect to morphology and immunohistochemical profiles. Macrophage iNOS immunoreactivity was detected 1 week after infection in one out of four rats and was strongly expressed in all rats at 2 weeks (in up to 50% of the granulomas) but declined considerably by 25 days. iNOS expression coincided with granuloma formation and preceded a decrease in lung fungal burden, suggesting an anticryptococcal role for NO. By double labeling, cytokines that have been shown to promote (interferon-γ, granulocyte/macrophage colony-stimulating factor) and inhibit (transforming growth factor-β) macrophage iNOS expression were detected around iNOS+ granulomas. iNOS immunoreactivity was expressed in selected neutrophils (1 and 2 weeks) and endothelial cells (1 and 2 weeks and 25 days) in the inflamed lung. Airway iNOS immunoreactivity was limited to the luminal border of rare bronchiolar epithelial cells. iNOS immunoreactivity was not detected in uninfected rats. The present study provides the first evidence for association of iNOS expression with protective cellular responses to cryptococcal infection in vivo.

Original languageEnglish (US)
Pages (from-to)1275-1282
Number of pages8
JournalAmerican Journal of Pathology
Volume148
Issue number4
StatePublished - Apr 1996
Externally publishedYes

Fingerprint

Cryptococcus neoformans
Nitric Oxide Synthase Type II
Granuloma
Lung
Macrophages
Nitric Oxide
Infection
Neutrophils
Immunohistochemistry
Cytokines
Cryptococcosis
Respiratory Mucosa
Vascular Endothelium
Transforming Growth Factors
Granulocyte-Macrophage Colony-Stimulating Factor

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Expression of inducible nitric oxide synthase in rat pulmonary Cryptococcus neoformans granulomas. / Goldman, David; Cho, Youngsoo; Zhao, Meng Liang; Casadevall, Arturo; Lee, Sunhee C.

In: American Journal of Pathology, Vol. 148, No. 4, 04.1996, p. 1275-1282.

Research output: Contribution to journalArticle

Goldman, David ; Cho, Youngsoo ; Zhao, Meng Liang ; Casadevall, Arturo ; Lee, Sunhee C. / Expression of inducible nitric oxide synthase in rat pulmonary Cryptococcus neoformans granulomas. In: American Journal of Pathology. 1996 ; Vol. 148, No. 4. pp. 1275-1282.
@article{50e6fb53ed764d8f90386850fdac572a,
title = "Expression of inducible nitric oxide synthase in rat pulmonary Cryptococcus neoformans granulomas",
abstract = "Rats, like humans, have extremely effective immune mechanisms for controlling pulmonary Cryptococcus neoformans infection. The mechanism(s) responsible for efficient immunity in rat experimental infection is unknown. Recently, induction of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) have been implicated as an important microbicidal mechanism by which activated macrophages effect cytotoxicity against microbes. In this report, we investigated the expression of iNOS in rat pulmonary cryptococcosis. Localization and regulation of NO production was studied by immunohistochemistry for iNOS in conjunction with immunohistochemistry for cell markers, cytokines, and cryptococcal capsular polysaccharide. iNOS immunoreactivity was detected in macrophages, neutrophils, vascular endothelium, and respiratory epithelium. Double-immunolabeling studies revealed that the most prominent iNOS immunoreactivity was localized to epithelioid macrophages (CD11b/c+) within granulomas; CD4+ and CD8+ T cells were numerous around granulomas but did not express iNOS. iNOS immunoreactivity was detected in a selective population of epithelioid macrophages within some granulomas but not others. iNOS- granulomas were identical to iNOS+ granulomas with respect to morphology and immunohistochemical profiles. Macrophage iNOS immunoreactivity was detected 1 week after infection in one out of four rats and was strongly expressed in all rats at 2 weeks (in up to 50{\%} of the granulomas) but declined considerably by 25 days. iNOS expression coincided with granuloma formation and preceded a decrease in lung fungal burden, suggesting an anticryptococcal role for NO. By double labeling, cytokines that have been shown to promote (interferon-γ, granulocyte/macrophage colony-stimulating factor) and inhibit (transforming growth factor-β) macrophage iNOS expression were detected around iNOS+ granulomas. iNOS immunoreactivity was expressed in selected neutrophils (1 and 2 weeks) and endothelial cells (1 and 2 weeks and 25 days) in the inflamed lung. Airway iNOS immunoreactivity was limited to the luminal border of rare bronchiolar epithelial cells. iNOS immunoreactivity was not detected in uninfected rats. The present study provides the first evidence for association of iNOS expression with protective cellular responses to cryptococcal infection in vivo.",
author = "David Goldman and Youngsoo Cho and Zhao, {Meng Liang} and Arturo Casadevall and Lee, {Sunhee C.}",
year = "1996",
month = "4",
language = "English (US)",
volume = "148",
pages = "1275--1282",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "4",

}

TY - JOUR

T1 - Expression of inducible nitric oxide synthase in rat pulmonary Cryptococcus neoformans granulomas

AU - Goldman, David

AU - Cho, Youngsoo

AU - Zhao, Meng Liang

AU - Casadevall, Arturo

AU - Lee, Sunhee C.

PY - 1996/4

Y1 - 1996/4

N2 - Rats, like humans, have extremely effective immune mechanisms for controlling pulmonary Cryptococcus neoformans infection. The mechanism(s) responsible for efficient immunity in rat experimental infection is unknown. Recently, induction of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) have been implicated as an important microbicidal mechanism by which activated macrophages effect cytotoxicity against microbes. In this report, we investigated the expression of iNOS in rat pulmonary cryptococcosis. Localization and regulation of NO production was studied by immunohistochemistry for iNOS in conjunction with immunohistochemistry for cell markers, cytokines, and cryptococcal capsular polysaccharide. iNOS immunoreactivity was detected in macrophages, neutrophils, vascular endothelium, and respiratory epithelium. Double-immunolabeling studies revealed that the most prominent iNOS immunoreactivity was localized to epithelioid macrophages (CD11b/c+) within granulomas; CD4+ and CD8+ T cells were numerous around granulomas but did not express iNOS. iNOS immunoreactivity was detected in a selective population of epithelioid macrophages within some granulomas but not others. iNOS- granulomas were identical to iNOS+ granulomas with respect to morphology and immunohistochemical profiles. Macrophage iNOS immunoreactivity was detected 1 week after infection in one out of four rats and was strongly expressed in all rats at 2 weeks (in up to 50% of the granulomas) but declined considerably by 25 days. iNOS expression coincided with granuloma formation and preceded a decrease in lung fungal burden, suggesting an anticryptococcal role for NO. By double labeling, cytokines that have been shown to promote (interferon-γ, granulocyte/macrophage colony-stimulating factor) and inhibit (transforming growth factor-β) macrophage iNOS expression were detected around iNOS+ granulomas. iNOS immunoreactivity was expressed in selected neutrophils (1 and 2 weeks) and endothelial cells (1 and 2 weeks and 25 days) in the inflamed lung. Airway iNOS immunoreactivity was limited to the luminal border of rare bronchiolar epithelial cells. iNOS immunoreactivity was not detected in uninfected rats. The present study provides the first evidence for association of iNOS expression with protective cellular responses to cryptococcal infection in vivo.

AB - Rats, like humans, have extremely effective immune mechanisms for controlling pulmonary Cryptococcus neoformans infection. The mechanism(s) responsible for efficient immunity in rat experimental infection is unknown. Recently, induction of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) have been implicated as an important microbicidal mechanism by which activated macrophages effect cytotoxicity against microbes. In this report, we investigated the expression of iNOS in rat pulmonary cryptococcosis. Localization and regulation of NO production was studied by immunohistochemistry for iNOS in conjunction with immunohistochemistry for cell markers, cytokines, and cryptococcal capsular polysaccharide. iNOS immunoreactivity was detected in macrophages, neutrophils, vascular endothelium, and respiratory epithelium. Double-immunolabeling studies revealed that the most prominent iNOS immunoreactivity was localized to epithelioid macrophages (CD11b/c+) within granulomas; CD4+ and CD8+ T cells were numerous around granulomas but did not express iNOS. iNOS immunoreactivity was detected in a selective population of epithelioid macrophages within some granulomas but not others. iNOS- granulomas were identical to iNOS+ granulomas with respect to morphology and immunohistochemical profiles. Macrophage iNOS immunoreactivity was detected 1 week after infection in one out of four rats and was strongly expressed in all rats at 2 weeks (in up to 50% of the granulomas) but declined considerably by 25 days. iNOS expression coincided with granuloma formation and preceded a decrease in lung fungal burden, suggesting an anticryptococcal role for NO. By double labeling, cytokines that have been shown to promote (interferon-γ, granulocyte/macrophage colony-stimulating factor) and inhibit (transforming growth factor-β) macrophage iNOS expression were detected around iNOS+ granulomas. iNOS immunoreactivity was expressed in selected neutrophils (1 and 2 weeks) and endothelial cells (1 and 2 weeks and 25 days) in the inflamed lung. Airway iNOS immunoreactivity was limited to the luminal border of rare bronchiolar epithelial cells. iNOS immunoreactivity was not detected in uninfected rats. The present study provides the first evidence for association of iNOS expression with protective cellular responses to cryptococcal infection in vivo.

UR - http://www.scopus.com/inward/record.url?scp=0029871993&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029871993&partnerID=8YFLogxK

M3 - Article

VL - 148

SP - 1275

EP - 1282

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 4

ER -