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Metabolic consequences of adenosine deaminase deficiency in mice are associated with defects in alveogenesis, pulmonary inflammation, and airway obstruction.

Blackburn MR, Volmer JB, Thrasher JL, Zhong H, Crosby JR, Lee JJ, Kellems RE - J. Exp. Med. (2000)

Bottom Line: These changes were accompanied by a pronounced enlargement of alveolar spaces and increases in mucus production in the bronchial airways.The alveolar enlargement was found to be due in part to abnormal alveogenesis.Lowering adenosine and 2'-deoxyadenosine levels using ADA enzyme therapy decreased the pulmonary eosinophilia and resolved many of the lung histopathologies.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston Medical School, Houston, Texas 77030, USA. blackburn@uth.tmc.edu

ABSTRACT
Adenosine deaminase (ADA) is a purine catabolic enzyme that manages levels of the biologically active purines adenosine and 2'-deoxyadenosine in tissues and cells. ADA-deficient mice die at 3 wk of age from severe respiratory distress. This phenotype is progressive and is linked to perturbations in pulmonary purine metabolism. The inflammatory changes found in the lungs of ADA-deficient mice included an accumulation of activated alveolar macrophages and eosinophils. These changes were accompanied by a pronounced enlargement of alveolar spaces and increases in mucus production in the bronchial airways. The alveolar enlargement was found to be due in part to abnormal alveogenesis. Lowering adenosine and 2'-deoxyadenosine levels using ADA enzyme therapy decreased the pulmonary eosinophilia and resolved many of the lung histopathologies. In addition, genetically restoring ADA to the forestomach of otherwise ADA-deficient mice prevented adenine metabolic disturbances as well as lung inflammation and damage. These data suggest that disturbances in purinergic signaling mediate the lung inflammation and damage seen in ADA-deficient mice.

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Defects in alveogenesis in ADA-deficient mice. Lungs from age-matched control and ADA-deficient mice were collected and processed for H&E staining. (a) Control lung at postpartum day 0. (b) ADA-deficient lung at day 0. (c) Control lung at day 5. (d) ADA-deficient lung at day 5. (e) Control lung at day 10 demonstrating the septation of presumptive alveoli into mature alveolar sacs. (f) ADA-deficient lung at day 10 demonstrating enlarged alveolar spaces. Panels a–f are at the same magnification; bars, 250 μm. (g) The size of alveolar airways was determined in control (white bars, n = 4) and ADA-deficient (black bars, n = 4) lungs by measuring mean chord lengths (in μm) of alveolar airways in H&E-stained lungs. Values are given as mean μm ± SE from four separate age-matched control and ADA-deficient lung pairs at each developmental stage; *P ≤ 0.05.
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Figure 3: Defects in alveogenesis in ADA-deficient mice. Lungs from age-matched control and ADA-deficient mice were collected and processed for H&E staining. (a) Control lung at postpartum day 0. (b) ADA-deficient lung at day 0. (c) Control lung at day 5. (d) ADA-deficient lung at day 5. (e) Control lung at day 10 demonstrating the septation of presumptive alveoli into mature alveolar sacs. (f) ADA-deficient lung at day 10 demonstrating enlarged alveolar spaces. Panels a–f are at the same magnification; bars, 250 μm. (g) The size of alveolar airways was determined in control (white bars, n = 4) and ADA-deficient (black bars, n = 4) lungs by measuring mean chord lengths (in μm) of alveolar airways in H&E-stained lungs. Values are given as mean μm ± SE from four separate age-matched control and ADA-deficient lung pairs at each developmental stage; *P ≤ 0.05.

Mentions: The severe inflammation and damage seen on day 18 prompted us to examine the development of this phenotype. At birth, control and ADA-deficient lungs were histologically similar (Fig. 3, a and b). At postpartum day 5, the overall morphology (Fig. 3c and Fig. d) suggested that there was an increase in alveolar airway size. Secondary septation of the alveoli occurred between postpartum days 5 and 10 in control mice (Fig. 3 e); however, alveolar size remained enlarged in ADA-deficient lungs at postpartum day 10 (Fig. 3 f). Quantitation of alveolar size (Fig. 3 g) verified that there was a significant difference in alveolar size at day 5, suggesting that alveolar formation in ADA-deficient mice was disturbed early in life and worsened by day 10. Lung inflammation was not seen in ADA-deficient lungs at day 0 and day 5 as determined by H&E staining (Fig. 3) and mMBP-1 immunostaining (data not shown). Slight inflammation was seen at day 10 (Fig. 3 f), and increased numbers of alveolar macrophages and eosinophils were consistently seen at day 15 (data not shown; 15). These results demonstrated that there was a defect in alveogenesis in ADA-deficient mice and that these defects preceded the appearance of lung inflammation.


Metabolic consequences of adenosine deaminase deficiency in mice are associated with defects in alveogenesis, pulmonary inflammation, and airway obstruction.

Blackburn MR, Volmer JB, Thrasher JL, Zhong H, Crosby JR, Lee JJ, Kellems RE - J. Exp. Med. (2000)

Defects in alveogenesis in ADA-deficient mice. Lungs from age-matched control and ADA-deficient mice were collected and processed for H&E staining. (a) Control lung at postpartum day 0. (b) ADA-deficient lung at day 0. (c) Control lung at day 5. (d) ADA-deficient lung at day 5. (e) Control lung at day 10 demonstrating the septation of presumptive alveoli into mature alveolar sacs. (f) ADA-deficient lung at day 10 demonstrating enlarged alveolar spaces. Panels a–f are at the same magnification; bars, 250 μm. (g) The size of alveolar airways was determined in control (white bars, n = 4) and ADA-deficient (black bars, n = 4) lungs by measuring mean chord lengths (in μm) of alveolar airways in H&E-stained lungs. Values are given as mean μm ± SE from four separate age-matched control and ADA-deficient lung pairs at each developmental stage; *P ≤ 0.05.
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Related In: Results  -  Collection

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Figure 3: Defects in alveogenesis in ADA-deficient mice. Lungs from age-matched control and ADA-deficient mice were collected and processed for H&E staining. (a) Control lung at postpartum day 0. (b) ADA-deficient lung at day 0. (c) Control lung at day 5. (d) ADA-deficient lung at day 5. (e) Control lung at day 10 demonstrating the septation of presumptive alveoli into mature alveolar sacs. (f) ADA-deficient lung at day 10 demonstrating enlarged alveolar spaces. Panels a–f are at the same magnification; bars, 250 μm. (g) The size of alveolar airways was determined in control (white bars, n = 4) and ADA-deficient (black bars, n = 4) lungs by measuring mean chord lengths (in μm) of alveolar airways in H&E-stained lungs. Values are given as mean μm ± SE from four separate age-matched control and ADA-deficient lung pairs at each developmental stage; *P ≤ 0.05.
Mentions: The severe inflammation and damage seen on day 18 prompted us to examine the development of this phenotype. At birth, control and ADA-deficient lungs were histologically similar (Fig. 3, a and b). At postpartum day 5, the overall morphology (Fig. 3c and Fig. d) suggested that there was an increase in alveolar airway size. Secondary septation of the alveoli occurred between postpartum days 5 and 10 in control mice (Fig. 3 e); however, alveolar size remained enlarged in ADA-deficient lungs at postpartum day 10 (Fig. 3 f). Quantitation of alveolar size (Fig. 3 g) verified that there was a significant difference in alveolar size at day 5, suggesting that alveolar formation in ADA-deficient mice was disturbed early in life and worsened by day 10. Lung inflammation was not seen in ADA-deficient lungs at day 0 and day 5 as determined by H&E staining (Fig. 3) and mMBP-1 immunostaining (data not shown). Slight inflammation was seen at day 10 (Fig. 3 f), and increased numbers of alveolar macrophages and eosinophils were consistently seen at day 15 (data not shown; 15). These results demonstrated that there was a defect in alveogenesis in ADA-deficient mice and that these defects preceded the appearance of lung inflammation.

Bottom Line: These changes were accompanied by a pronounced enlargement of alveolar spaces and increases in mucus production in the bronchial airways.The alveolar enlargement was found to be due in part to abnormal alveogenesis.Lowering adenosine and 2'-deoxyadenosine levels using ADA enzyme therapy decreased the pulmonary eosinophilia and resolved many of the lung histopathologies.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston Medical School, Houston, Texas 77030, USA. blackburn@uth.tmc.edu

ABSTRACT
Adenosine deaminase (ADA) is a purine catabolic enzyme that manages levels of the biologically active purines adenosine and 2'-deoxyadenosine in tissues and cells. ADA-deficient mice die at 3 wk of age from severe respiratory distress. This phenotype is progressive and is linked to perturbations in pulmonary purine metabolism. The inflammatory changes found in the lungs of ADA-deficient mice included an accumulation of activated alveolar macrophages and eosinophils. These changes were accompanied by a pronounced enlargement of alveolar spaces and increases in mucus production in the bronchial airways. The alveolar enlargement was found to be due in part to abnormal alveogenesis. Lowering adenosine and 2'-deoxyadenosine levels using ADA enzyme therapy decreased the pulmonary eosinophilia and resolved many of the lung histopathologies. In addition, genetically restoring ADA to the forestomach of otherwise ADA-deficient mice prevented adenine metabolic disturbances as well as lung inflammation and damage. These data suggest that disturbances in purinergic signaling mediate the lung inflammation and damage seen in ADA-deficient mice.

Show MeSH
Related in: MedlinePlus