Agonist of growth hormone-releasing hormone reduces pneumolysin-induced pulmonary permeability edema

Rudolf Lucas, Supriya Sridhar, Ferenc G. Rick, Boris A Gorshkov, Umapathy N Siddaramappa, Guang Yang, Aluya Oseghale, Alexander Dmitriyevich Verin, Trinad Chakraborty, Michael A. Matthay, Evgeny Alexandrovich Zemskov, Richard White, Norman L. Block, Andrew V. Schally

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Aggressive treatment with antibiotics in patients infected with Streptococcus pneumoniae induces release of the bacterial virulence factor pneumolysin (PLY). Days after lungs are sterile, this pore-forming toxin can still induce pulmonary permeability edema in patients, characterized by alveolar/capillary barrier dysfunction and impaired alveolar liquid clearance (ALC). ALC is mainly regulated through Na + transport by the apically expressed epithelial sodium channel (ENaC) and the basolaterally expressed Na +/K +- ATPase in type II alveolar epithelial cells. Because no standard treatment is currently available to treat permeability edema, the search for novel therapeutic candidates is of high priority. We detected mRNA expression for the active receptor splice variant SV1 of the hypothalamic polypeptide growth hormone-releasing hormone (GHRH), as well as for GHRH itself, in human lung microvascular endothelial cells (HL-MVEC). Therefore, we have evaluated the effect of the GHRH agonist JI-34 on PLY-induced barrier and ALC dysfunction. JI-34 blunts PLY-mediated endothelial hyperpermeability in monolayers of HL-MVEC, in a cAMP-dependent manner, by means of reducing the phosphorylation of myosin light chain and vascular endothelial (VE)-cadherin. In human airway epithelial H441 cells, PLY significantly impairs Na + uptake, but JI-34 restores it to basal levels by means of increasing cAMP levels. Intratracheal instillation of PLY into C57BL6 mice causes pulmonary alveolar epithelial and endothelial hyperpermeability as well as edema formation, all of which are blunted by JI-34. These findings point toward a protective role of the GHRH signaling pathway in PLY-induced permeability edema.

Original languageEnglish (US)
Pages (from-to)2084-2089
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number6
DOIs
StatePublished - Feb 7 2012

Keywords

  • Cyclic AMP
  • Pneumonia

ASJC Scopus subject areas

  • General

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