Lung fluid absorption is induced in preterm guinea pigs ventilated with low tidal volumes.
Time Factors; Animals; Gestational Age; Guinea Pigs; *Premature Birth; Phosphorylation; Enzyme Activation; Permeability; Extracellular Signal-Regulated MAP Kinases/metabolism; Intubation; Epithelial Sodium Channels/metabolism; Absorption; Sodium-Potassium-Exchanging ATPase/metabolism; Fetal Organ Maturity; Epinephrine/blood; Extravascular Lung Water/*metabolism; *Tidal Volume; Albumins/administration & dosage/*metabolism; Hydrocortisone/blood; Lung/embryology/*metabolism/physiopathology; MAP Kinase Kinase Kinases/metabolism; Ventilator-Induced Lung Injury/metabolism/physiopathology/*prevention & control; Newborn; Intratracheal; Artificial/adverse effects/*methods; Respiration
The objective of this study was to determine if low tidal volume (V(t)) ventilation was beneficial when ventilating preterm fetuses. The authors ventilated preterm guinea pig fetuses at gestation day (GD) 67, 3 days before birth, newborn, and 10-day-old (PD10) guinea pigs with low V(t) (6 mL/kg body weight [bw]) and compared them to age-matched fetuses/animals ventilated with higher potentially injurious V(t) (12 mL/kg bw). Lung fluid absorption was measured after intratracheal instillation of 5% albumin in 0.9% NaCl. Low V(t) ventilation stimulated lung fluid absorption when compared to higher V(t) in all groups. The increased lung fluid absorption in low V(t)-ventilated fetuses was associated with increased alpha epithelial Na channel (alphaEnaC) mRNA. However, alphaENaC and betaENaC protein was unchanged over the 1-hour study. Because stretch induces mitogen-activated protein (MAP) kinase expression and MAP kinases may affect lung fluid absorption, the authors investigated if MAP kinase (MAPK) expression was affected by V(t). Extracellular signal-regulated kinase (ERK) and MAPK/ERK kinase (MEK) were phosphorylated in the higher V(t)-ventilated guinea pig fetuses. This suggested that a reduced activation of MAP kinases might explain the increased lung fluid absorption in the low V(t)-ventilated fetuses. Thus these data suggest that low V(t) ventilation increases fetal lung fluid absorption and thus may be preferential to use clinically.
Koshy Shyny; Beard LaMonta L; Kuzenko Stephanie R; Li Tianbo; Folkesson Hans G
Experimental lung research
2011
2011-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3109/01902148.2010.514024" target="_blank" rel="noreferrer noopener">10.3109/01902148.2010.514024</a>
The adenosine 2A receptor agonist GW328267C improves lung function after acute lung injury in rats.
Acute Lung Injury/*drug therapy/metabolism/pathology; Adenosine A2A/*chemistry; Adenosine/*analogs & derivatives/therapeutic use; Amiloride/pharmacology; Animals; Biological Transport; Bronchoalveolar Lavage; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism; Endotoxemia/*drug therapy/metabolism/microbiology; Epithelial Sodium Channel Blockers; Epithelial Sodium Channels/metabolism; Escherichia coli; Escherichia coli Infections/drug therapy/metabolism/microbiology; Immunoblotting; Male; Pneumonia/*drug therapy/metabolism/microbiology; Pulmonary Alveoli/cytology/*drug effects/metabolism; Pulmonary Edema/*drug therapy/metabolism/pathology; Rats; Receptor; Respiratory Physiological Phenomena; Sodium Channel Blockers/pharmacology; Sprague-Dawley; Triazoles/*therapeutic use
There is a significant unmet need for treatments of patients with acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS). The primary mechanism that leads to resolution of alveolar and pulmonary edema is active vectorial Na(+) and Cl(-) transport across the alveolar epithelium. Several studies have suggested a role for adenosine receptors in regulating this fluid transport in the lung. Furthermore, these studies point to the A(2A) subtype of adenosine receptor (A(2A)R) as playing a role to enhance fluid transport, suggesting that activation of the A(2A)R may enhance alveolar fluid clearance (AFC). The current studies test the potential therapeutic value of the A(2A)R agonist GW328267C to accelerate resolution of alveolar edema and ALI/ARDS in rats. GW328267C, at concentrations of 10(-5) M to 10(-3) M, instilled into the airspaces, increased AFC in control animals. GW328267C did not increase AFC beyond that produced by maximal beta-adrenergic stimulation. The effect of GW328267C was inhibited by amiloride but was not affected by cystic fibrosis transmembrane conductance regulator inhibition. The drug was tested in three models of ALI, HCl instillation 1 h, LPS instillation 16 h, and live Escherichia coli instillation 2 h before GW328267C instillation. After either type of injury, GW328267C (10(-4) M) decreased pulmonary edema formation and restored AFC, measured 1 h after GW328267C instillation. These findings show that GW328267C has beneficial effects in experimental models of ALI and may be a useful agent for treating patients with ALI or prophylactically to prevent ALI.
Folkesson Hans G; Kuzenko Stephanie R; Lipson David A; Matthay Michael A; Simmons Mark A
American journal of physiology. Lung cellular and molecular physiology
2012
2012-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajplung.00395.2011" target="_blank" rel="noreferrer noopener">10.1152/ajplung.00395.2011</a>
Virtual screening to identify novel antagonists for the G protein-coupled NK3 receptor.
*Models; *Narcotic Antagonists; *Quantitative Structure-Activity Relationship; Animals; Binding; Calcium Signaling/drug effects; CHO Cells; Competitive; Cricetinae; Cricetulus; Databases; Factual; Humans; Ligands; Molecular; Neurokinin-3/*antagonists & inhibitors/chemistry; Opioid/chemistry; Quinolines/*chemistry/pharmacology; Radioligand Assay; Receptors
The NK(3) subtype of tachykinin receptor is a G protein-coupled receptor that is a potential therapeutic target for several neurological diseases, including schizophrenia. In this study, we have screened compound databases for novel NK(3) receptor antagonists using a virtual screening protocol of similarity analysis. The lead compound for this study was the potent NK(3) antagonist talnetant. Compounds of the quinoline type found in the virtual screen were additionally evaluated in a comparative molecular field analysis model to predict activity a priori to testing in vitro. Selected members of this latter set were tested for their ability to inhibit ligand binding to the NK(3) receptor as well as to inhibit senktide-induced calcium responses in cells expressing the human NK(3) receptor. Two novel compounds were identified that inhibited NK(3) receptor agonist binding, with potencies in the nM range and antagonized NK(3) receptor-mediated increases in intracellular calcium. These results demonstrate the utility of similarity analysis in identifying novel antagonist ligands for neuropeptide receptors.
Geldenhuys Werner J; Kuzenko Stephanie R; Simmons Mark A
Journal of medicinal chemistry
2010
2010-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1021/jm1010012" target="_blank" rel="noreferrer noopener">10.1021/jm1010012</a>