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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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Pulmonary disease in X-CGD mice after administration of  A. fumigatus conidia. (a) Lung tissue obtained 11 d after challenge with  540 A. fumigatus conidia and stained with hematoxylin and eosin. Note  areas of neutrophil inflammation surrounded by mononuclear cells (original magnification of 100). (b) Grocott methamine stain of lung from  X-CGD mouse with neutrophil inflammation; note branching filamentous hyphae (original magnification of 100). (c) Grocott methamine silver  staining of the same tissue shown in a with no visible hyphae (original  magnification of 100). (d) Lung tissue obtained 21 d after challenge with  48 conidia and stained with hematoxylin and eosin. Low power view of a  representative inflammatory lesion showing nodular region of inflammation and destruction of underlying lung tissue (original magnification of  100). (e) Higher power view of chronic inflammatory lesion consisting of  neutrophils, epithelioid macrophages, and giant cells (original magnification of 400).
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Figure 2: Pulmonary disease in X-CGD mice after administration of A. fumigatus conidia. (a) Lung tissue obtained 11 d after challenge with 540 A. fumigatus conidia and stained with hematoxylin and eosin. Note areas of neutrophil inflammation surrounded by mononuclear cells (original magnification of 100). (b) Grocott methamine stain of lung from X-CGD mouse with neutrophil inflammation; note branching filamentous hyphae (original magnification of 100). (c) Grocott methamine silver staining of the same tissue shown in a with no visible hyphae (original magnification of 100). (d) Lung tissue obtained 21 d after challenge with 48 conidia and stained with hematoxylin and eosin. Low power view of a representative inflammatory lesion showing nodular region of inflammation and destruction of underlying lung tissue (original magnification of 100). (e) Higher power view of chronic inflammatory lesion consisting of neutrophils, epithelioid macrophages, and giant cells (original magnification of 400).

Mentions: Gross and histologic abnormalities after A. fumigatus respiratory challenge were observed in the lungs of all X-CGD mice at all doses of conidia studied. X-CGD mice that died or were moribund within the first week after Aspergillus challenge had similar pathology. Histologic findings, which included extensive peribronchiolar and alveolar inflammation consisting of neutrophils, necrotic debris, and edema, were similar to that previously described for X-CGD mice challenged with 3 × 106 conidia (not shown) (15). In X-CGD mice that survived beyond 1 wk, chronic inflammatory changes became more evident. Areas of almost complete neutrophil consolidation surrounded by a more diffuse mononuclear cell infiltrate and edema were a common finding (Fig. 2 a), as was the formation of wellcircumscribed abscesses (not shown). Intact hyphae, as visualized by silver staining, were detected in all X-CGD mice challenged with Aspergillus. Regions with an extensive neutrophil infiltrate typically contained numerous hyphae (Fig. 2 b), while areas of chronic inflammation had few hyphae (not shown). However, occasional regions with numerous focal collections of neutrophils did not contain detectable hyphae (Fig. 2 c). In X-CGD mice who survived for more than 2 wk after Aspergillus challenge, chronic inflammatory lesions were typically distributed in a nodular pattern and were comprised largely of mononuclear cells (Fig. 2 d) along with other cell types frequently associated with granulomatous inflammation including large, highly vacuolated macrophages (foam cells; not shown) and giant cells (Fig. 2 e). Neutrophils were often present in the centers of these nodules (Fig. 2 e), and occasionally, necrotic debris (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)

Pulmonary disease in X-CGD mice after administration of  A. fumigatus conidia. (a) Lung tissue obtained 11 d after challenge with  540 A. fumigatus conidia and stained with hematoxylin and eosin. Note  areas of neutrophil inflammation surrounded by mononuclear cells (original magnification of 100). (b) Grocott methamine stain of lung from  X-CGD mouse with neutrophil inflammation; note branching filamentous hyphae (original magnification of 100). (c) Grocott methamine silver  staining of the same tissue shown in a with no visible hyphae (original  magnification of 100). (d) Lung tissue obtained 21 d after challenge with  48 conidia and stained with hematoxylin and eosin. Low power view of a  representative inflammatory lesion showing nodular region of inflammation and destruction of underlying lung tissue (original magnification of  100). (e) Higher power view of chronic inflammatory lesion consisting of  neutrophils, epithelioid macrophages, and giant cells (original magnification of 400).
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Related In: Results  -  Collection

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Figure 2: Pulmonary disease in X-CGD mice after administration of A. fumigatus conidia. (a) Lung tissue obtained 11 d after challenge with 540 A. fumigatus conidia and stained with hematoxylin and eosin. Note areas of neutrophil inflammation surrounded by mononuclear cells (original magnification of 100). (b) Grocott methamine stain of lung from X-CGD mouse with neutrophil inflammation; note branching filamentous hyphae (original magnification of 100). (c) Grocott methamine silver staining of the same tissue shown in a with no visible hyphae (original magnification of 100). (d) Lung tissue obtained 21 d after challenge with 48 conidia and stained with hematoxylin and eosin. Low power view of a representative inflammatory lesion showing nodular region of inflammation and destruction of underlying lung tissue (original magnification of 100). (e) Higher power view of chronic inflammatory lesion consisting of neutrophils, epithelioid macrophages, and giant cells (original magnification of 400).
Mentions: Gross and histologic abnormalities after A. fumigatus respiratory challenge were observed in the lungs of all X-CGD mice at all doses of conidia studied. X-CGD mice that died or were moribund within the first week after Aspergillus challenge had similar pathology. Histologic findings, which included extensive peribronchiolar and alveolar inflammation consisting of neutrophils, necrotic debris, and edema, were similar to that previously described for X-CGD mice challenged with 3 × 106 conidia (not shown) (15). In X-CGD mice that survived beyond 1 wk, chronic inflammatory changes became more evident. Areas of almost complete neutrophil consolidation surrounded by a more diffuse mononuclear cell infiltrate and edema were a common finding (Fig. 2 a), as was the formation of wellcircumscribed abscesses (not shown). Intact hyphae, as visualized by silver staining, were detected in all X-CGD mice challenged with Aspergillus. Regions with an extensive neutrophil infiltrate typically contained numerous hyphae (Fig. 2 b), while areas of chronic inflammation had few hyphae (not shown). However, occasional regions with numerous focal collections of neutrophils did not contain detectable hyphae (Fig. 2 c). In X-CGD mice who survived for more than 2 wk after Aspergillus challenge, chronic inflammatory lesions were typically distributed in a nodular pattern and were comprised largely of mononuclear cells (Fig. 2 d) along with other cell types frequently associated with granulomatous inflammation including large, highly vacuolated macrophages (foam cells; not shown) and giant cells (Fig. 2 e). Neutrophils were often present in the centers of these nodules (Fig. 2 e), and occasionally, necrotic debris (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