Monocyte mRNA phenotype and adverse outcomes from pediatric multiple organ dysfunction syndrome.
Impairment of the ability to mount an inflammatory response is associated with death from adult critical illness. This phenomenon, characterized by reduced monocyte production of proinflammatory mediators such as tumor necrosis factor alpha (TNF-alpha), is poorly understood in children. We hypothesized that differential expression of inflammation-related genes would be seen in monocytes from children with adverse outcomes from multiple organ dysfunction syndrome (MODS). Ex vivo lipopolysaccharide (LPS)-induced TNF-alpha production and plasma cytokines were prospectively measured biweekly in children with dysfunction of two or more organs. Concomitantly, monocyte expression of 28 pro- and anti-inflammatory genes [cytokines, Toll-like receptor (TLR)/nuclear factor kappaB (NF-kappaB) signaling pathway members, inflammasome elements] was measured. Thirty children (22 survivors, eight nonsurvivors) were evaluated. High mRNA levels for interleukin (IL)-10, IL-1 receptor-associated kinase (IRAK-M), and the putative inflammasome inhibitor pyrin were associated with death (p < or = 0.02). Plasma IL-10 levels were higher and ex vivo TNF-alpha production was lower in nonsurvivors (p < 0.05). Among survivors, high mRNA levels for IL-10, IRAK-M, pyrin, IRAK1, or TLR4 were associated with longer durations of pediatric intensive care unit (PICU) stay and mechanical ventilation (p < or = 0.02). These data suggest that adverse outcomes from pediatric MODS are associated with an anti-inflammatory monocyte mRNA phenotype. Future studies are warranted to explore mechanisms of immunodepression in pediatric critical illness.
Hall
Mark W
MW
Department of Pediatrics, Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, Ohio 43210, USA. hallma@pediatrics.ohio-state.edu
Gavrilin
Mikhail A
MA
Knatz
Nina L
NL
Duncan
Michelle D
MD
Fernandez
Soledad A
SA
Wewers
Mark D
MD
D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000097:blood* / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000097:blood; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007249:Inflammation / Q000097:blood* / Q000235:genetics; D018836:Inflammation Mediators / Q000097:blood*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D007902:Length of Stay; D008070:Lipopolysaccharides / Q000494:pharmacology; D008137:Longitudinal Studies; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D009102:Multiple Organ Failure / Q000097:blood* / Q000235:genetics / Q000401:mortality; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D011446:Prospective Studies; D000071198:Pyrin; D012333:RNA, Messenger / Q000097:blood*; D012107:Research Design; D012121:Respiration, Artificial; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000097:blood; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D015854:Up-Regulation