Lung pathologies in a chronic inflammation mouse model are independent of eosinophil degranulation

Elizabeth Jacobsen, Sergei I. Ochkur, Alfred D. Doyle, William E. LeSuer, Wen Li, Cheryl A. Protheroe, Dana Colbert, Katie R. Zellner, Huahao H. Shen, Charles G. Irvin, James J. Lee, Nancy A Lee

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Rationale: The release of eosinophil granule proteins in the lungs of patients with asthma has been dogmatically linked with lung remodeling and airway hyperresponsiveness. However, the demonstrated inability of established mouse models to display the eosinophil degranulation occurring in human subjects has prevented adefinitive in vivo test of this hypothesis. Objectives: To demonstrate in vivo causative links between induced pulmonary histopathologies/lung dysfunction and eosinophil degranulation. Methods: A transgenic mouse model of chronic T-helper cell type 2-driven inflammation overexpressing IL-5 from T cells and human eotaxin 2 in the lung (I5/hE2) was used to test the hypothesis that chronic histopathologies and the development of airway hyperresponsiveness occur as a consequence of extensive eosinophil degranulation in the lung parenchyma. Measurement and Main Results: Studies targeting specific inflammatory pathways in I5/hE2 mice surprisingly showed that eosinophil-dependent immunoregulative events and not the release of individual secondary granule proteins are the central contributors to T-helper cell type 2-induced pulmonary remodeling and lung dysfunction. Specifically, our studies highlighted a significant role for eosinophil-dependent IL-13 expression. In contrast, extensive degranulation leading to the release of major basic protein-1 or eosinophil peroxidase was not causatively linked to many of the induced pulmonary histopathologies. However, these studies did define a previously unappreciated link between the release of eosinophil peroxidase (but not major basic protein-1) and observed levels of induced airway mucin. Conclusions: These data suggest that improvements observed in patients with asthma responding to therapeutic strategies ablating eosinophils may occur as a consequence of targeting immunoregulatory mechanisms and not by simply eliminating the destructive activities of these purportedly end-stage effector cells.

Original languageEnglish (US)
Pages (from-to)1321-1332
Number of pages12
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume195
Issue number10
DOIs
StatePublished - May 15 2017

Fingerprint

Eosinophils
Pathology
Inflammation
Lung
Eosinophil Peroxidase
Th2 Cells
Chemokine CCL24
Eosinophil Granule Proteins
Asthma
Airway Remodeling
Proteins
Interleukin-13
Interleukin-5
Mucins
Transgenic Mice
T-Lymphocytes

Keywords

  • Asthma
  • Chronic inflammation
  • Eosinophil peroxidase
  • Lung
  • Major basic protein

ASJC Scopus subject areas

  • Medicine(all)
  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Lung pathologies in a chronic inflammation mouse model are independent of eosinophil degranulation. / Jacobsen, Elizabeth; Ochkur, Sergei I.; Doyle, Alfred D.; LeSuer, William E.; Li, Wen; Protheroe, Cheryl A.; Colbert, Dana; Zellner, Katie R.; Shen, Huahao H.; Irvin, Charles G.; Lee, James J.; Lee, Nancy A.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 195, No. 10, 15.05.2017, p. 1321-1332.

Research output: Contribution to journalArticle

Jacobsen, E, Ochkur, SI, Doyle, AD, LeSuer, WE, Li, W, Protheroe, CA, Colbert, D, Zellner, KR, Shen, HH, Irvin, CG, Lee, JJ & Lee, NA 2017, 'Lung pathologies in a chronic inflammation mouse model are independent of eosinophil degranulation', American Journal of Respiratory and Critical Care Medicine, vol. 195, no. 10, pp. 1321-1332. https://doi.org/10.1164/rccm.201606-1129OC
Jacobsen, Elizabeth ; Ochkur, Sergei I. ; Doyle, Alfred D. ; LeSuer, William E. ; Li, Wen ; Protheroe, Cheryl A. ; Colbert, Dana ; Zellner, Katie R. ; Shen, Huahao H. ; Irvin, Charles G. ; Lee, James J. ; Lee, Nancy A. / Lung pathologies in a chronic inflammation mouse model are independent of eosinophil degranulation. In: American Journal of Respiratory and Critical Care Medicine. 2017 ; Vol. 195, No. 10. pp. 1321-1332.
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AU - Protheroe, Cheryl A.

AU - Colbert, Dana

AU - Zellner, Katie R.

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