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Absence of respiratory burst in X-linked chronic granulomatous disease mice leads to abnormalities in both host defense and inflammatory response to Aspergillus fumigatus.

Morgenstern DE, Gifford MA, Li LL, Doerschuk CM, Dinauer MC - J. Exp. Med. (1997)

Bottom Line: This opportunistic fungal pathogen causes infection in CGD patients due to the deficient generation of neutrophil respiratory burst oxidants important for damaging A. fumigatus hyphae.Alveolar macrophages from X-CGD mice were found to kill A. fumigatus conidia in vitro as effectively as alveolar macrophages from wild-type mice.This is the first experimental evidence that chronic inflammation in CGD does not always result from persistent infection, and suggests that the clinical manifestations of this disorder reflect both impaired microbial killing as well as other abnormalities in the inflammatory response in the absence of a respiratory burst.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics (Hematology-Oncology), Indiana University Medical Center, Indianapolis 46202, USA.

ABSTRACT
Mice with X-linked chronic granulomatous disease (CGD) generated by targeted disruption of the gp91phox subunit of the NADPH-oxidase complex (X-CGD mice) were examined for their response to respiratory challenge with Aspergillus fumigatus. This opportunistic fungal pathogen causes infection in CGD patients due to the deficient generation of neutrophil respiratory burst oxidants important for damaging A. fumigatus hyphae. Alveolar macrophages from X-CGD mice were found to kill A. fumigatus conidia in vitro as effectively as alveolar macrophages from wild-type mice. Pulmonary disease in X-CGD mice was observed after administration of doses ranging from 10(5) to 48 spores, none of which produced disease in wild-type mice. Higher doses produced a rapidly fatal bronchopneumonia in X-CGD mice, whereas progression of disease was slower at lower doses, with development of chronic inflammatory lesions. Marked differences were also observed in the response of X-CGD mice to the administration of sterilized Aspergillus hyphae into the lung. Within 24 hours of administration, X-CGD mice had significantly higher numbers of alveolar neutrophils and increased expression of the proinflammatory cytokines IL-1 beta and TNF-alpha relative to the responses seen in wild-type mice. By one week after administration, pulmonary inflammation was resolving in wild-type mice, whereas X-CGD mice developed chronic granulomatous lesions that persisted for at least six weeks. This is the first experimental evidence that chronic inflammation in CGD does not always result from persistent infection, and suggests that the clinical manifestations of this disorder reflect both impaired microbial killing as well as other abnormalities in the inflammatory response in the absence of a respiratory burst.

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Morphometric analysis of lung sections 24 and 72 h after  challenge with sterile A. fumigatus hyphae. Lung tissue was obtained either  24 or 72 h after intratracheal administration of 5 μg of sterile hyphae. 100  randomly selected alveoli containing carbon were scored for numbers of  neutrophils, large mononuclear cells, and small mononuclear cells. Data are  expressed as mean ± SD. Open bars, wild-type mice; filled bars, X-CGD  mice. *, significantly different from wild type (P <0.0005, t test); ‡, significantly different from wild type (P <0.05, t test); §, significantly different  from wild type (P <0.005, t test).
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Figure 4: Morphometric analysis of lung sections 24 and 72 h after challenge with sterile A. fumigatus hyphae. Lung tissue was obtained either 24 or 72 h after intratracheal administration of 5 μg of sterile hyphae. 100 randomly selected alveoli containing carbon were scored for numbers of neutrophils, large mononuclear cells, and small mononuclear cells. Data are expressed as mean ± SD. Open bars, wild-type mice; filled bars, X-CGD mice. *, significantly different from wild type (P <0.0005, t test); ‡, significantly different from wild type (P <0.05, t test); §, significantly different from wild type (P <0.005, t test).

Mentions: Morphometric analysis of the inflammatory cell infiltrate elicited by intratracheal administration of sterile hyphal fragments was also performed to obtain a quantitative measure of the differences between wild-type and X-CGD mice. At both 24 and 72 h, the neutrophils were the predominant cell type in both X-CGD and wild-type alveoli (Fig. 4). However, X-CGD mice had almost five times the amount of neutrophils as wild-type controls. The number of mononuclear cells was also significantly higher (almost double) in X-CGD mice compared to wild-type mice 72 h after administration of hyphae (Fig. 4). No differences in the peripheral leukocyte counts were observed between wild-type and X-CGD mice at either of these time points (data not shown).


Absence of respiratory burst in X-linked chronic granulomatous disease mice leads to abnormalities in both host defense and inflammatory response to Aspergillus fumigatus.

Morgenstern DE, Gifford MA, Li LL, Doerschuk CM, Dinauer MC - J. Exp. Med. (1997)

Morphometric analysis of lung sections 24 and 72 h after  challenge with sterile A. fumigatus hyphae. Lung tissue was obtained either  24 or 72 h after intratracheal administration of 5 μg of sterile hyphae. 100  randomly selected alveoli containing carbon were scored for numbers of  neutrophils, large mononuclear cells, and small mononuclear cells. Data are  expressed as mean ± SD. Open bars, wild-type mice; filled bars, X-CGD  mice. *, significantly different from wild type (P <0.0005, t test); ‡, significantly different from wild type (P <0.05, t test); §, significantly different  from wild type (P <0.005, t test).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196125&req=5

Figure 4: Morphometric analysis of lung sections 24 and 72 h after challenge with sterile A. fumigatus hyphae. Lung tissue was obtained either 24 or 72 h after intratracheal administration of 5 μg of sterile hyphae. 100 randomly selected alveoli containing carbon were scored for numbers of neutrophils, large mononuclear cells, and small mononuclear cells. Data are expressed as mean ± SD. Open bars, wild-type mice; filled bars, X-CGD mice. *, significantly different from wild type (P <0.0005, t test); ‡, significantly different from wild type (P <0.05, t test); §, significantly different from wild type (P <0.005, t test).
Mentions: Morphometric analysis of the inflammatory cell infiltrate elicited by intratracheal administration of sterile hyphal fragments was also performed to obtain a quantitative measure of the differences between wild-type and X-CGD mice. At both 24 and 72 h, the neutrophils were the predominant cell type in both X-CGD and wild-type alveoli (Fig. 4). However, X-CGD mice had almost five times the amount of neutrophils as wild-type controls. The number of mononuclear cells was also significantly higher (almost double) in X-CGD mice compared to wild-type mice 72 h after administration of hyphae (Fig. 4). No differences in the peripheral leukocyte counts were observed between wild-type and X-CGD mice at either of these time points (data not shown).

Bottom Line: This opportunistic fungal pathogen causes infection in CGD patients due to the deficient generation of neutrophil respiratory burst oxidants important for damaging A. fumigatus hyphae.Alveolar macrophages from X-CGD mice were found to kill A. fumigatus conidia in vitro as effectively as alveolar macrophages from wild-type mice.This is the first experimental evidence that chronic inflammation in CGD does not always result from persistent infection, and suggests that the clinical manifestations of this disorder reflect both impaired microbial killing as well as other abnormalities in the inflammatory response in the absence of a respiratory burst.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics (Hematology-Oncology), Indiana University Medical Center, Indianapolis 46202, USA.

ABSTRACT
Mice with X-linked chronic granulomatous disease (CGD) generated by targeted disruption of the gp91phox subunit of the NADPH-oxidase complex (X-CGD mice) were examined for their response to respiratory challenge with Aspergillus fumigatus. This opportunistic fungal pathogen causes infection in CGD patients due to the deficient generation of neutrophil respiratory burst oxidants important for damaging A. fumigatus hyphae. Alveolar macrophages from X-CGD mice were found to kill A. fumigatus conidia in vitro as effectively as alveolar macrophages from wild-type mice. Pulmonary disease in X-CGD mice was observed after administration of doses ranging from 10(5) to 48 spores, none of which produced disease in wild-type mice. Higher doses produced a rapidly fatal bronchopneumonia in X-CGD mice, whereas progression of disease was slower at lower doses, with development of chronic inflammatory lesions. Marked differences were also observed in the response of X-CGD mice to the administration of sterilized Aspergillus hyphae into the lung. Within 24 hours of administration, X-CGD mice had significantly higher numbers of alveolar neutrophils and increased expression of the proinflammatory cytokines IL-1 beta and TNF-alpha relative to the responses seen in wild-type mice. By one week after administration, pulmonary inflammation was resolving in wild-type mice, whereas X-CGD mice developed chronic granulomatous lesions that persisted for at least six weeks. This is the first experimental evidence that chronic inflammation in CGD does not always result from persistent infection, and suggests that the clinical manifestations of this disorder reflect both impaired microbial killing as well as other abnormalities in the inflammatory response in the absence of a respiratory burst.

Show MeSH
Related in: MedlinePlus