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

Rudolf Lucas1, Supriya Sridhar, Ferenc G Rick

  • 1Vascular Biology Center and Department of Pharmacology and Toxicology, Georgia Health Sciences University, Augusta, GA 30912, USA. rlucas@georgiahealth.edu

Proceedings of the National Academy of Sciences of the United States of America
|February 7, 2012
PubMed

Insights

Growth hormone-releasing hormone (GHRH) agonist JI-34 effectively treats lung injury caused by pneumolysin (PLY). JI-34 protects against PLY-induced pulmonary edema and barrier dysfunction, offering a potential new therapy.

Area of Science:

  • Pulmonary Medicine
  • Cell Biology
  • Pharmacology

Background:

  • Streptococcus pneumoniae infection and antibiotic treatment can trigger pneumolysin (PLY) release, causing lung injury.
  • PLY induces pulmonary permeability edema, characterized by alveolar/capillary barrier dysfunction and impaired alveolar liquid clearance (ALC), even after bacteria are cleared.
  • Current treatments for PLY-induced edema are lacking, necessitating the development of novel therapeutic strategies.

Purpose of the Study:

  • To investigate the therapeutic potential of a growth hormone-releasing hormone (GHRH) agonist, JI-34, in mitigating pneumolysin (PLY)-induced lung injury.
  • To elucidate the mechanisms by which GHRH signaling impacts PLY-induced pulmonary endothelial and epithelial barrier dysfunction.

Main Methods:

  • Assessed the effect of JI-34 on PLY-induced hyperpermeability in human lung microvascular endothelial cells (HL-MVEC) and human airway epithelial H441 cells.
  • Measured changes in cAMP levels, myosin light chain, and vascular endothelial (VE)-cadherin phosphorylation.
  • Evaluated the efficacy of JI-34 in a mouse model of PLY-induced pulmonary edema via intratracheal instillation.

Main Results:

  • JI-34 significantly reduced PLY-mediated hyperpermeability in HL-MVEC by decreasing myosin light chain and VE-cadherin phosphorylation in a cAMP-dependent manner.
  • In H441 cells, JI-34 restored PLY-impaired sodium uptake to basal levels by increasing cAMP.
  • Intratracheal administration of JI-34 attenuated PLY-induced pulmonary edema, epithelial, and endothelial hyperpermeability in mice.

Conclusions:

  • The GHRH signaling pathway plays a protective role in combating PLY-induced lung injury.
  • GHRH agonist JI-34 demonstrates significant therapeutic potential for treating pneumolysin-induced pulmonary permeability edema.
  • Targeting GHRH signaling represents a promising novel therapeutic approach for managing lung injury associated with Streptococcus pneumoniae infections.

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