Integrated Stress Response Mediates Epithelial Injury in Mechanical Ventilation.

Ventilator-induced lung injury (VILI) is a severe complication of mechanical ventilation that can lead to acute respiratory distress syndrome. VILI is characterized by damage to the epithelial barrier with subsequent pulmonary edema and profound hypoxia. Available lung-protective ventilator strategies offer only a modest benefit in preventing VILI because they cannot impede alveolar overdistension and concomitant epithelial barrier dysfunction in the inflamed lung regions. There are currently no effective biochemical therapies to mitigate injury to the alveolar epithelium. We hypothesize that alveolar stretch activates the integrated stress response (ISR) pathway and that the chemical inhibition of this pathway mitigates alveolar barrier disruption during stretch and mechanical ventilation. Using our established rat primary type I-like alveolar epithelial cell monolayer stretch model and in vivo rat mechanical ventilation that mimics the alveolar overdistension seen in acute respiratory distress syndrome, we studied epithelial responses to mechanical stress. Our studies revealed that the ISR signaling pathway is a key modulator of epithelial permeability. We show that prolonged epithelial stretch and injurious mechanical ventilation activate the ISR, leading to increased alveolar permeability, cell death, and proinflammatory signaling. Chemical inhibition of protein kinase RNA-like endoplasmic reticulum kinase, an upstream regulator of the pathway, resulted in decreased injury signaling and improved barrier function after prolonged cyclic stretch and injurious mechanical ventilation. Our results provide new evidence that therapeutic targeting of the ISR can mitigate VILI.

[Randomised placebo controlled double blind study on the effect of prebiotic oligosaccharides on intestinal flora in healthy infants]. / Prebiotikus hatású oligoszacharidok egészséges csecsemok székletflórájára gyakorolt hatásának randomizált, placébóval kontrollált vizsgálata.

AIM: Effects of supplementing prebiotic oligosaccharides to formula for healthy infants were studied in this placebo controlled, randomised, double blind study. METHODS: Ninety-seven infants were included into the study; among them 42 breast-fed infants, 14 infants fed formula supplemented with 0.4 g/100ml oligosaccharides (9 to 1 mixture of galacto- and fructooligosaccharides) and 13 infants fed control formula were followed-up throughout the 12-week-long study period. The groups receiving formula were compared with statistical methods, whereas data of breast-fed infants served as reference values. RESULTS: Infants fed the two formulae did not differ in nutrient intakes, growth, occurrence rate of feeding difficulties and atopic manifestations, or in calcium excretion. The intestinal flora did not differ between the two formula fed groups at the beginning of the study. In contrast, numbers of Bifidobacteriae were significantly higher in infants receiving the formula supplemented with prebiotic oligosaccharides both at the 14th day (9 x 1011 versus 5 x 1010, colony forming units/g faeces, median, p < 0.05) and 28th day (9 x 1012 versus 5 x 1010, p < 0.05) of the study. CONCLUSION: In this study, supplementation of infant formula with prebiotic oligosaccharides resulted in ameliorating the difference in intestinal flora between formula fed and breast-fed healthy infants.