Subcutaneous administration of neutralizing antibodies to endothelial monocyte-activating protein II attenuates cigarette smoke-induced lung injury in mice

Kengo Koike, Erica L. Beatman, Kelly S. Schweitzer, Matthew J. Justice, Andrew M. Mikosz, Kevin Ni, Matthias Clauss, Irina Petrache

Research output: Contribution to journalArticle

Abstract

Subcutaneous administration of neutralizing antibodies to endothelial monocyte-activating protein II attenuates cigarette smoke-induced lung injury in mice. Am J Physiol Lung Cell Mol Physiol 316: L558–L566, 2019. First published January 10, 2019; doi:10.1152/ajplung.00409.2018.—Proapoptotic and monocyte chemotactic endothelial monocyte-activating protein 2 (EMAPII) is released extracellularly during cigarette smoke (CS) exposure. We have previously demonstrated that, when administered intratracheally during chronic CS exposures, neutralizing rat antibodies to EMAPII inhibited endothelial cell apoptosis and lung inflammation and reduced airspace enlargement in mice (DBA/2J strain). Here we report further preclinical evaluation of EMAPII targeting using rat anti-EMAPII antibodies via either nebulization or subcutaneous injection. Both treatment modalities efficiently ameliorated emphysema-like disease in two different strains of CS-exposed mice, DBA/2J and C57BL/6. Of relevance for clinical applicability, this treatment showed therapeutic and even curative potential when administered either during or following CS-induced emphysema development, respectively. In addition, a fully humanized neutralizing anti-EMAPII antibody administered subcutaneously to mice during CS exposure retained anti-apoptotic and anti-inflammatory effects similar to that of the parent rat antibody. Furthermore, humanized anti-EMAPII antibody treatment attenuated CS-induced autophagy and restored mammalian target of rapamycin signaling in the lungs of mice, despite ongoing CS exposure. Together, our results demonstrate that EMAPII secretion is involved in CS-induced lung inflammation and cell injury, including apoptosis and autophagy, and that a humanized EMAPII neutralizing antibody may have therapeutic potential in emphysema.

Original languageEnglish (US)
Pages (from-to)L558-L566
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume316
Issue number3
DOIs
StatePublished - Mar 1 2019
Externally publishedYes

Fingerprint

Lung Injury
Neutralizing Antibodies
Smoke
Tobacco Products
Monocytes
Proteins
Emphysema
Anti-Idiotypic Antibodies
Inbred DBA Mouse
Autophagy
Pneumonia
Apoptosis
Therapeutics
Antibodies, Monoclonal, Humanized
Lung
Sirolimus
Subcutaneous Injections
Inbred C57BL Mouse
Anti-Inflammatory Agents
Endothelial Cells

Keywords

  • Apoptosis
  • Autophagy
  • Chronic obstructive pulmonary disease
  • Endothelium
  • Pulmonary emphysema

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Cite this

Subcutaneous administration of neutralizing antibodies to endothelial monocyte-activating protein II attenuates cigarette smoke-induced lung injury in mice. / Koike, Kengo; Beatman, Erica L.; Schweitzer, Kelly S.; Justice, Matthew J.; Mikosz, Andrew M.; Ni, Kevin; Clauss, Matthias; Petrache, Irina.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 316, No. 3, 01.03.2019, p. L558-L566.

Research output: Contribution to journalArticle

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