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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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Inflammatory response in wild-type and X-CGD mice lungs 21 d after challenge with sterile A. fumigatus hyphae. Lung tissue was obtained  21 d after intratracheal administration of 5 μg of sterile hyphae and stained with hematoxylin and eosin. (a) Representative section of lung from a wild-type  mouse. Inflammation has largely resolved, although some residual edema and peribronchiolar inflammation remain (original magnification of 100). (b)  Lung from X-CGD mouse with scattered nodular inflammatory foci (original magnification of 100). (c) Lung from X-CGD mouse with almost complete  consolidation and destruction of lung parenchyma (original magnification of 100). (d) Higher power of area in 6 b, showing central neutrophil microabscess and surrounding epithelioid cells (original magnification of 400).
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Figure 5: Inflammatory response in wild-type and X-CGD mice lungs 21 d after challenge with sterile A. fumigatus hyphae. Lung tissue was obtained 21 d after intratracheal administration of 5 μg of sterile hyphae and stained with hematoxylin and eosin. (a) Representative section of lung from a wild-type mouse. Inflammation has largely resolved, although some residual edema and peribronchiolar inflammation remain (original magnification of 100). (b) Lung from X-CGD mouse with scattered nodular inflammatory foci (original magnification of 100). (c) Lung from X-CGD mouse with almost complete consolidation and destruction of lung parenchyma (original magnification of 100). (d) Higher power of area in 6 b, showing central neutrophil microabscess and surrounding epithelioid cells (original magnification of 400).

Mentions: One week after administration of 5 μg of sterile hyphal fragments, 11 out of 13 wild-type mice still had evidence of a mild, diffuse alveolar pneumonia, consisting of neutrophils and mononuclear cells (not shown). In two wildtype mice, a more severe chronic inflammatory response developed, characterized by extensive infiltration of alveoli with large mononuclear cells and a fibrinous exudate (not shown). In contrast, at 1 wk, 8 out of 8 X-CGD mice were found to have a distinctive granuloma-like inflammatory infiltrate consisting of neutrophil microabscesses surrounded by large mononuclear cells with an epithelioid morphology (not shown). By 21 d, the contrast between wild-type and X-CGD mice was even more striking. The pneumonia in 3 out of 3 wild-type mice had almost entirely resolved (Fig. 5 a), whereas 3 out of 3 X-CGD mice still had numerous inflammatory nodules (Fig. 5 b) which often become confluent (Fig. 5 c). These foci continued to show a characteristic granuloma-like structure, with a central area of neutrophils surrounded by epithelioid mononuclear cells (Fig. 5 d). Lungs obtained from 3 of 3 X-CGD mice 6 wk after administration of sterile hyphal fragments showed persistence of these inflammatory lesions. No evidence of hyphal growth was evident in Grocott methamine silver–stained sections (not shown), and cultures of lungs from X-CGD mice killed at 1 wk showed no growth of fungi and grew similar numbers of bacteria to that observed in wild-type mice (<1 × 104 cfu/lung).


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)

Inflammatory response in wild-type and X-CGD mice lungs 21 d after challenge with sterile A. fumigatus hyphae. Lung tissue was obtained  21 d after intratracheal administration of 5 μg of sterile hyphae and stained with hematoxylin and eosin. (a) Representative section of lung from a wild-type  mouse. Inflammation has largely resolved, although some residual edema and peribronchiolar inflammation remain (original magnification of 100). (b)  Lung from X-CGD mouse with scattered nodular inflammatory foci (original magnification of 100). (c) Lung from X-CGD mouse with almost complete  consolidation and destruction of lung parenchyma (original magnification of 100). (d) Higher power of area in 6 b, showing central neutrophil microabscess and surrounding epithelioid cells (original magnification of 400).
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Related In: Results  -  Collection

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Figure 5: Inflammatory response in wild-type and X-CGD mice lungs 21 d after challenge with sterile A. fumigatus hyphae. Lung tissue was obtained 21 d after intratracheal administration of 5 μg of sterile hyphae and stained with hematoxylin and eosin. (a) Representative section of lung from a wild-type mouse. Inflammation has largely resolved, although some residual edema and peribronchiolar inflammation remain (original magnification of 100). (b) Lung from X-CGD mouse with scattered nodular inflammatory foci (original magnification of 100). (c) Lung from X-CGD mouse with almost complete consolidation and destruction of lung parenchyma (original magnification of 100). (d) Higher power of area in 6 b, showing central neutrophil microabscess and surrounding epithelioid cells (original magnification of 400).
Mentions: One week after administration of 5 μg of sterile hyphal fragments, 11 out of 13 wild-type mice still had evidence of a mild, diffuse alveolar pneumonia, consisting of neutrophils and mononuclear cells (not shown). In two wildtype mice, a more severe chronic inflammatory response developed, characterized by extensive infiltration of alveoli with large mononuclear cells and a fibrinous exudate (not shown). In contrast, at 1 wk, 8 out of 8 X-CGD mice were found to have a distinctive granuloma-like inflammatory infiltrate consisting of neutrophil microabscesses surrounded by large mononuclear cells with an epithelioid morphology (not shown). By 21 d, the contrast between wild-type and X-CGD mice was even more striking. The pneumonia in 3 out of 3 wild-type mice had almost entirely resolved (Fig. 5 a), whereas 3 out of 3 X-CGD mice still had numerous inflammatory nodules (Fig. 5 b) which often become confluent (Fig. 5 c). These foci continued to show a characteristic granuloma-like structure, with a central area of neutrophils surrounded by epithelioid mononuclear cells (Fig. 5 d). Lungs obtained from 3 of 3 X-CGD mice 6 wk after administration of sterile hyphal fragments showed persistence of these inflammatory lesions. No evidence of hyphal growth was evident in Grocott methamine silver–stained sections (not shown), and cultures of lungs from X-CGD mice killed at 1 wk showed no growth of fungi and grew similar numbers of bacteria to that observed in wild-type mice (<1 × 104 cfu/lung).

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