Mechanisms of allergy and clinical immunology
Induction of a disintegrin and metalloprotease 33 during embryonic lung development and the influence of IL-13 or maternal allergy

https://doi.org/10.1016/j.jaci.2009.06.026Get rights and content

Background

Asthma pathogenesis involves gene and environmental interactions. A disintegrin and metalloprotease 33 (ADAM33)/Adam33 is a susceptibility gene for asthma and bronchial hyperresponsiveness in human beings and mice. ADAM33 is almost exclusively expressed in mesenchymal cells, including mesenchymal progenitors in developing lungs.

Objective

Because maternal allergy is a risk factor for asthma, we hypothesized that an allergic environment affects ADAM33/Adam33 expression during human and mouse lung development.

Methods

Human embryonic/fetal lung (HEL) tissues were collected from first-trimester terminations of pregnancy. These were processed immediately or used for explant culture ± IL-13. MF1 mice or ovalbumin-sensitized A/J mice (Bronchial hyperresponsivness (Bhr)1/Adam33 locus–positive) were time-mated and challenged with ovalbumin (A/J mice only) during pregnancy. Lungs were harvested at different times during gestation and post partum. ADAM33/Adam33 expression was analyzed by using reverse transcriptase quantitative polymerase chain reaction and Western blotting.

Results

ADAM33 mRNA was detectable in HELs in the pseudoglandular stage of development and showed a significant increase from 7 to 9 weeks postconception. IL-13 significantly suppressed ADAM33 mRNA in HEL explants. In developing murine lungs, Adam33 mRNA and protein expression increased significantly in the early pseudoglandular stage and showed another large increase post partum. In A/J mice, maternal allergy significantly suppressed Adam33 mRNA in lungs of newborn pups, whereas processed Adam33 protein increased and several smaller isoforms were detected.

Conclusion

Adam33/Adam33 shows 2 significant increments in expression during lung morphogenesis, suggesting important developmental regulation. The ability of maternal allergy or exogenous IL-13 to suppress Adam33/ADAM33 mRNA but enhance Adam33 processing suggests a gene-environment interaction that may be relevant for asthma pathogenesis.

Section snippets

Methods

Additional details of all Methods can be found in this article's Online Repository at www.jacionline.org.

ADAM33 mRNA expression in HELs in vivo

To study the expression of ADAM33 mRNA in HELs, RNA was extracted from fresh HELs obtained 7 to 9 weeks postconception. Comparisons during the early pseudoglandular stage of lung development suggested that ADAM33 mRNA expression increased significantly from 7 to 9 weeks postconception (Fig 1, A). When HEL tissues were dissected into the tubular structure and the mesenchyme surrounding these structures, ADAM33 mRNA expression was significantly higher in the mesenchyme (Fig 1, B), confirming our

Discussion

In this study, we show for the first time that ADAM33/Adam33 expression is developmentally regulated in human and murine lungs. Furthermore, although mRNA expression is suppressed by maternal allergy or exogenous IL-13, in vivo Adam33 protein is increased in lungs from 4-day-old offspring of mothers with ovalbumin allergy, suggesting important gene-environment interactions that may contribute to asthma pathogenesis. We have previously shown that ADAM33 can be found almost exclusively in the

References (38)

  • H. Jongepier et al.

    Polymorphisms of the ADAM33 gene are associated with accelerated lung function decline in asthma

    Clin Exp Allergy

    (2004)
  • C.C. van Diemen et al.

    A disintegrin and metalloprotease 33 polymorphisms and lung function decline in the general population

    Am J Respir Crit Care Med

    (2005)
  • A. Simpson et al.

    Polymorphisms in a disintegrin and metalloprotease 33 (ADAM33) predict impaired early-life lung function

    Am J Respir Crit Care Med

    (2005)
  • G.T. De Sanctis et al.

    Quantitative locus analysis of airway hyperresponsiveness in A/J and C57BL/6J mice

    Nat Genet

    (1995)
  • T.M. Gunn et al.

    Identification and preliminary characterization of mouse Adam33

    BMC Genet

    (2002)
  • S.P. Umland et al.

    Human ADAM33 messenger RNA expression profile and post-transcriptional regulation

    Am J Respir Cell Mol Biol

    (2003)
  • Y. Yang et al.

    Epigenetic mechanisms silence a disintegrin and metalloprotease 33 expression in bronchial epithelial cells

    J Allergy Clin Immunol

    (2008)
  • J.Y. Lee et al.

    A disintegrin and metalloproteinase 33 protein in patients with asthma: relevance to airflow limitation

    Am J Respir Crit Care Med

    (2006)
  • I. Puxeddu et al.

    The soluble form of a disintegrin and metalloprotease 33 promotes angiogenesis: implications for airway remodeling in asthma

    J Allergy Clin Immunol

    (2008)
  • Cited by (23)

    • A prenatally disrupted airway epithelium orchestrates the fetal origin of asthma in mice

      2020, Journal of Allergy and Clinical Immunology
      Citation Excerpt :

      Postnatally, Sftpa expression was not determined, as analysis of Sftpc expression provides sufficient insight into the maturation of AEC type II, which showed no significant differences between groups. Next, the expression of the transcription factor SRY-Box 9 (Sox9), which is involved in the transition from branching morphogenesis to alveolar epithelial terminal differentiation,63 and disintegrin and metalloproteinase domain-containing protein 33 (Adam33), an asthma susceptibility gene associated with lung development,64 was assessed. Prenatal stress challenge did not significantly affect the expression of these markers, but a reduced expression pattern was observed in the female lung (see Fig E6, F).

    • Genetics in Asthma and COPD

      2015, Murray and Nadel's Textbook of Respiratory Medicine: Volume 1,2, Sixth Edition
    • Mouse Models of Allergic Airways Disease

      2014, Middleton's Allergy: Principles and Practice: Eighth Edition
    • ADAM33

      2013, Handbook of Proteolytic Enzymes
    • Normal Lung Function from Childhood to Old Age

      2020, Cotes’ Lung Function, Seventh Edition
    View all citing articles on Scopus

    Disclosure of potential conflict of interest: D. J. P. Bassett and X. Gao have received research support from the Michigan University Challenge Initiative, Synairgen Research Ltd, and Wayne State University Research Enhancement. D. I. Wilson has received research support from the Engineering and Physical Sciences Research Council UK. The rest of the authors have declared that they have no conflict of interest.

    Supported by the Asthma, Allergy and Inflammation Research (AAIR) Charity, the British Lung Foundation, the Medical Research Council, and the Roger Brooke Charitable Trust, United Kingdom; and Research Enhancement Funds, Wayne State University, Detroit, Mich.

    View full text