G protein-regulated endocytic trafficking of adenylyl cyclase type 9

GPCRs are increasingly recognized to initiate signaling via heterotrimeric G proteins as they move through the endocytic network, but little is known about how relevant G protein effectors are localized. Here we report selective trafficking of adenylyl cyclase type 9 (AC9) from the plasma membrane to endosomes while adenylyl cyclase type 1 (AC1) remains in the plasma membrane, and stimulation of AC9 trafficking by ligand-induced activation of Gs-coupled GPCRs. AC9 transits a similar, dynamin-dependent early endocytic pathway as ligand-activated GPCRs. However, unlike GPCR traffic control which requires β-arrestin but not Gs, AC9 traffic control requires Gs but not β-arrestin. We also show that AC9, but not AC1, mediates cAMP production stimulated by endogenous receptor activation in endosomes. These results reveal dynamic and isoform-specific trafficking of adenylyl cyclase in the endocytic network, and a discrete role of a heterotrimeric G protein in regulating the subcellular distribution of a relevant effector

Hemodynamic changes in the kidney in a pediatric rat model of sepsis-induced acute kidney injury

Sepsis is a leading cause of acute kidney injury (AKI) and mortality in children. Understanding the development of pediatric sepsis and its effects on the kidney are critical in uncovering new therapies. The goal of this study was to characterize the development of sepsis-induced AKI in the clinically relevant cecal ligation and puncture (CLP) model of peritonitis in rat pups 17–18 days old. CLP produced severe sepsis demonstrated by time-dependent increase in serum cytokines, NO, markers of multiorgan injury, and renal microcirculatory hypoperfusion. Although blood pressure and heart rate remained unchanged after CLP, renal blood flow (RBF) was decreased 61% by 6 h. Renal microcirculatory analysis showed the number of continuously flowing cortical capillaries decreased significantly from 69 to 48% by 6 h with a 66% decrease in red blood cell velocity and a 57% decline in volumetric flow. The progression of renal microcirculatory hypoperfusion was associated with peritubular capillary leakage and reactive nitrogen species generation. Sham adults had higher mean arterial pressure (118 vs. 69 mmHg), RBF (4.2 vs. 1.1 ml·min−1·g−1), and peritubular capillary velocity (78% continuous flowing capillaries vs. 69%) compared with pups. CLP produced a greater decrease in renal microcirculation in pups, supporting the notion that adult models may not be the most appropriate for studying pediatric sepsis-induced AKI. Lower RBF and reduced peritubular capillary perfusion in the pup suggest the pediatric kidney may be more susceptible to AKI than would be predicted using adults models

Mechanical ventilation in pediatric intensive care units during the season for acute lower respiratory infection: a multicenter study

OBJECTIVE: To describe the characteristics and outcomes of mechanical ventilation in pediatric intensive care units during the season of acute lower respiratory infections. DESIGN: Prospective cohort of infants and children receiving mechanical ventilation for at least 12 hrs. SETTING: Sixty medical-surgical pediatric intensive care units. PATIENTS: All consecutive patients admitted to participating pediatric intensive care units during a 28-day period. MEASUREMENTS AND MAIN RESULTS: Of 2,156 patients admitted to pediatric intensive care units, 1185 (55%) received mechanical ventilation for a median of 5 days (interquartile range 2-8). Median age was 7 months (interquartile range 2-25). Main indications for mechanical ventilation were acute respiratory failure in 78% of the patients, altered mental status in 15%, and acute on chronic pulmonary disease in 6%. Median length of stay in the pediatric intensive care units was 10 days (interquartile range 6-18). Overall mortality rate in pediatric intensive care units was 13% (95% confidence interval: 11-15) for the entire population, and 39% (95% confidence interval: 23 - 58) in patients with acute respiratory distress syndrome. Of 1150 attempts at liberation from mechanical ventilation, 62% (95% confidence interval: 60-65) used the spontaneous breathing trial, and 37% (95% confidence interval: 35-40) used gradual reduction of ventilatory support. Noninvasive mechanical ventilation was used initially in 173 patients (15%, 95% confidence interval: 13-17). CONCLUSION: In the season of acute lower respiratory infections, one of every two children admitted to pediatric intensive care units requires mechanical ventilation. Acute respiratory failure was the most common reason for mechanical ventilation. The spontaneous breathing trial was the most commonly used method for liberation from mechanical ventilation

Mechanical ventilation in pediatric intensive care units during the season for acute lower respiratory infection: a multicenter study

OBJECTIVE: To describe the characteristics and outcomes of mechanical ventilation in pediatric intensive care units during the season of acute lower respiratory infections. DESIGN: Prospective cohort of infants and children receiving mechanical ventilation for at least 12 hrs. SETTING: Sixty medical-surgical pediatric intensive care units. PATIENTS: All consecutive patients admitted to participating pediatric intensive care units during a 28-day period. MEASUREMENTS AND MAIN RESULTS: Of 2,156 patients admitted to pediatric intensive care units, 1185 (55%) received mechanical ventilation for a median of 5 days (interquartile range 2-8). Median age was 7 months (interquartile range 2-25). Main indications for mechanical ventilation were acute respiratory failure in 78% of the patients, altered mental status in 15%, and acute on chronic pulmonary disease in 6%. Median length of stay in the pediatric intensive care units was 10 days (interquartile range 6-18). Overall mortality rate in pediatric intensive care units was 13% (95% confidence interval: 11-15) for the entire population, and 39% (95% confidence interval: 23 - 58) in patients with acute respiratory distress syndrome. Of 1150 attempts at liberation from mechanical ventilation, 62% (95% confidence interval: 60-65) used the spontaneous breathing trial, and 37% (95% confidence interval: 35-40) used gradual reduction of ventilatory support. Noninvasive mechanical ventilation was used initially in 173 patients (15%, 95% confidence interval: 13-17). CONCLUSION: In the season of acute lower respiratory infections, one of every two children admitted to pediatric intensive care units requires mechanical ventilation. Acute respiratory failure was the most common reason for mechanical ventilation. The spontaneous breathing trial was the most commonly used method for liberation from mechanical ventilation