Agonist of growth hormone-releasing hormone reduces pneumolysin-induced pulmonary permeability edema.
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.
Vascular Biology Center and Department of Pharmacology and Toxicology, Georgia Health Sciences University, Augusta, GA 30912, USA. rlucas@georgiahealth.edu
Rudolf
R
Lucas
Supriya
S
Sridhar
Ferenc G
FG
Rick
Boris
B
Gorshkov
Nagavedi S
NS
Umapathy
Guang
G
Yang
Aluya
A
Oseghale
Alexander D
AD
Verin
Trinad
T
Chakraborty
Michael A
MA
Matthay
Evgeny A
EA
Zemskov
Richard
R
White
Norman L
NL
Block
Andrew V
AV
Schally
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001426:Bacterial Proteins / Q000633:toxicity; D015820:Cadherins / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D013007:Growth Hormone-Releasing Hormone / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000473:pathology; D018994:Myosin Light Chains / Q000378:metabolism; D010539:Permeability; D010766:Phosphorylation; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000473:pathology; D011654:Pulmonary Edema / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D012326:RNA Splicing / Q000235:genetics; D018013:Receptors, Neuropeptide / Q000235:genetics / Q000378:metabolism; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000235:genetics / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism; D013301:Streptolysins / Q000633:toxicity*; D000099152:Cadherin 5
D015703:Antigens, CD; D001426:Bacterial Proteins; D015820:Cadherins; D013007:Growth Hormone-Releasing Hormone; D018994:Myosin Light Chains; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D015222:Sodium Channels; D013301:Streptolysins; D000099152:Cadherin 5; C032290:plY protein, Streptococcus pneumoniae; C048250:somatotropin releasing hormone receptor