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Agonist of growth hormone-releasing hormone reduces pneumolysin-induced pulmonary permeability edema.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2012 Feb 07; Vol. 109 (6), pp. 2084-9. Date of Electronic Publication: 2012 Jan 23. - Publication Year :
- 2012
-
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.
- Subjects :
- Animals
Antigens, CD metabolism
Bacterial Proteins toxicity
Cadherins metabolism
Endothelial Cells metabolism
Endothelial Cells pathology
Gene Expression Regulation
Growth Hormone-Releasing Hormone genetics
Growth Hormone-Releasing Hormone metabolism
Humans
Ion Channel Gating
Lung metabolism
Lung pathology
Mice
Mice, Inbred C57BL
Microvessels pathology
Myosin Light Chains metabolism
Permeability
Phosphorylation
Pulmonary Alveoli drug effects
Pulmonary Alveoli pathology
Pulmonary Edema genetics
Pulmonary Edema physiopathology
RNA Splicing genetics
Receptors, Neuropeptide genetics
Receptors, Neuropeptide metabolism
Receptors, Pituitary Hormone-Regulating Hormone genetics
Receptors, Pituitary Hormone-Regulating Hormone metabolism
Sodium Channels metabolism
Growth Hormone-Releasing Hormone agonists
Pulmonary Edema pathology
Streptolysins toxicity
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 109
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 22308467
- Full Text :
- https://doi.org/10.1073/pnas.1121075109