early-age-related changes in proteostasis augment immunopathogenesis of sepsis and acute lung injuryearly-age-related proteostasis变化增加脓毒症和急性肺损伤的免疫发病机理.pdfVIP

Early-Age-Related Changes in Proteostasis Augment Immunopathogenesis of Sepsis and Acute Lung Injury 1 1 1,2 Manish Bodas , Taehong Min , Neeraj Vij * 1 Department of Pediatric Respiratory Sciences, Johns Hopkins University, Baltimore, Maryland, United States of America, 2 Institute of Clinical and Translational Research, Johns Hopkins University, Baltimore, Maryland, United States of America Abstract Background: The decline of proteasomal activity is known to be associated with the age-related disorders but the early events involved in this process are not apparent. To address this, we investigated the early-age-related (pediatric vs. adult) mechanisms that augment immunopathogenesis of sepsis and acute lung injury. Methodology/Principal Findings: The 3-weeks (pediatric) and 6-months (adult) old C57BL/6 mice were selected as the study groups. Mice were subjected to 1 620 cecal ligation and puncture (CLP) mediated sepsis or intratracheal Psuedomonas aeruginosa (Pa)-LPS induced acute lung injury (ALI).We observed a significant increase in basal levels of pro-inflammatory cytokine, IL-6 and neutrophil activity marker, myeloperoxidase (MPO) in the adult mice compared to the pediatric indicating the age-related constitutive increase in inflammatory response. Next, we found that age-related decrease in PSMB6 (proteasomal subunit) expression in adult mice results in accumulation of ubiquitinated proteins that triggers the unfolded protein response (UPR). We identified that Pa-LPS induced activation of UPR modifier, p97/VCP (valosin-containing protein) in the adult mice lungs correlates with increase in Pa-LPS induced NFkB levels. Moreover, we observed a constitutive increase in p-eIF2a indicating a protective ER stress response to acc