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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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Lung inflammation in wild-type mice and X-CGD mice 24 h after challenge with sterile A. fumigatus hyphae. Lung tissue was obtained 24 h  after intratracheal administration of 5 μg of sterile hyphae and staining of representative sections with hematoxylin and eosin. (a) X-CGD lung with pneumonia and focal centers of neutrophil accumulation (original magnification of 400). (b) Lung from a wild-type mouse with comparatively mild, diffuse  neutrophil infiltrate. (original magnification of 400).
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Figure 3: Lung inflammation in wild-type mice and X-CGD mice 24 h after challenge with sterile A. fumigatus hyphae. Lung tissue was obtained 24 h after intratracheal administration of 5 μg of sterile hyphae and staining of representative sections with hematoxylin and eosin. (a) X-CGD lung with pneumonia and focal centers of neutrophil accumulation (original magnification of 400). (b) Lung from a wild-type mouse with comparatively mild, diffuse neutrophil infiltrate. (original magnification of 400).

Mentions: Striking differences in the appearance of the alveolar inflammatory infiltrate in wild-type versus X-CGD mice were evident even during the first 72 h after instillation of hyphae. At 24 h, an intense neutrophil alveolar infiltrate was seen in X-CGD mice, with foci of neutrophils often found in tight clusters around an eosinophilic center, with many cells assuming a spindle-shaped orientation towards the center of the inflammatory focus (Fig. 3 a). In contrast, in wild-type mice, the predominantly neutrophilic inflammatory infiltrate was diffusely scattered among alveoli without this focal pattern (Fig. 3 b). By 72 h, increased numbers of large mononuclear cells, debris, and a fibrinous exudate were seen in wild-type lung samples, again in a diffuse distribution (not shown). In X-CGD lung, focal accumulations of neutrophils were still numerous and were often surrounded by mononuclear cells (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)

Lung inflammation in wild-type mice and X-CGD mice 24 h after challenge with sterile A. fumigatus hyphae. Lung tissue was obtained 24 h  after intratracheal administration of 5 μg of sterile hyphae and staining of representative sections with hematoxylin and eosin. (a) X-CGD lung with pneumonia and focal centers of neutrophil accumulation (original magnification of 400). (b) Lung from a wild-type mouse with comparatively mild, diffuse  neutrophil infiltrate. (original magnification of 400).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Lung inflammation in wild-type mice and X-CGD mice 24 h after challenge with sterile A. fumigatus hyphae. Lung tissue was obtained 24 h after intratracheal administration of 5 μg of sterile hyphae and staining of representative sections with hematoxylin and eosin. (a) X-CGD lung with pneumonia and focal centers of neutrophil accumulation (original magnification of 400). (b) Lung from a wild-type mouse with comparatively mild, diffuse neutrophil infiltrate. (original magnification of 400).
Mentions: Striking differences in the appearance of the alveolar inflammatory infiltrate in wild-type versus X-CGD mice were evident even during the first 72 h after instillation of hyphae. At 24 h, an intense neutrophil alveolar infiltrate was seen in X-CGD mice, with foci of neutrophils often found in tight clusters around an eosinophilic center, with many cells assuming a spindle-shaped orientation towards the center of the inflammatory focus (Fig. 3 a). In contrast, in wild-type mice, the predominantly neutrophilic inflammatory infiltrate was diffusely scattered among alveoli without this focal pattern (Fig. 3 b). By 72 h, increased numbers of large mononuclear cells, debris, and a fibrinous exudate were seen in wild-type lung samples, again in a diffuse distribution (not shown). In X-CGD lung, focal accumulations of neutrophils were still numerous and were often surrounded by mononuclear cells (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