A Detailed Characterization of the Dysfunctional Immunity and Abnormal Myelopoiesis Induced by Severe Shock and Trauma in the Aged

Abstract

The elderly are particularly susceptible to trauma, and their outcomes are frequently dismal. Such patients often have complicated clinical courses and ultimately die from infection and sepsis. Recent research has revealed that although elderly subjects have increased baseline inflammation as compared to their younger counterparts, the elderly do not respond to severe infection/injury with an exaggerated inflammatory response. Initial retrospective analysis of clinical data from the Glue Grant trauma database demonstrated that despite a similar frequency, elderly trauma patients have worse outcomes to pneumonia than younger subjects. Subsequent analysis with a murine trauma model also demonstrated that elderly mice had increased mortality after post-trauma Pseudomonas pneumonia. Blood, bone marrow, and bronchoalveolar lavage sample analyses from juvenile and 20–24 month old mice showed that increased mortality to trauma combined with secondary infection in the aged are not due to an exaggerated inflammatory response. Rather, they are due to a failure of bone marrow progenitors, blood neutrophils, and bronchoalveolar lavage cells to initiate and complete an ‘emergency myelopoietic’ response, engendering myeloid cells that fail to clear secondary infection. In addition, the elderly appeared unable to effectively resolve their inflammatory response to severe injury.

Patterns of gene expression among murine models of hemorrhagic shock/trauma and sepsis

“…Thus, return to homeostasis is a key objective for future immunomodulation therapy of elderly trauma and sepsis patients (33,34,41). However, it is clear that juveniles do not return to baseline genomic expression patterns after severe trauma within 3 days in this study.…”

“…We have previously demonstrated that, in response to injury, the elderly do not have an exaggerated inflammatory response nor greater suppression of adaptive immunity genes but, rather, a delayed return to baseline (33,34,41). Thus, return to homeostasis is a key objective for future immunomodulation therapy of elderly trauma and sepsis patients (33,34,41).…”

“…Third, the findings are conducted in juvenile mice, and mortality from these conditions, especially sepsis, is most commonly associated with human patients of increased age (17,33). We have recently demonstrated that aged animals have a relatively attenuated early inflammatory response to both trauma and sepsis and fail to re-establish homeostasis (33,34). Furthermore, this study uses C57BL/6 mice, a Th1 dominant strain (44).…”

“…The bacterial density was measured at optical density 600 (DU 640 Spectrophotometer, Beckman Coulter, CA) and washed with saline. Under isoflurane anesthesia, these mice received intranasal instillation of 1 ϫ 10 7 bacteria, delivered in 50 l. This murine infection model has an LD10-20 over 7 days after polytrauma; it is a nonlethal model when administered to healthy animals (34).…”

Sex-based differences in the genomic response, innate immunity, organ dysfunction, and clinical outcomes after severe blunt traumatic injury and hemorrhagic shock

“…Additionally, Sperry et al have shown that polymorphism in the IRAK-1 component of the toll-like receptor response is a predictor of organ failure and mortality after severe injury. (25) Therefore, there may be non-hormonal, non-transcriptionally dependent pathways in innate immune signaling that are responsible for differences in the post-injury immune response and subsequent associated organ dysfunction. Given the ontology analysis also identified gene pathways associated with TGF-β response and protein catabolic pathways, it is interesting to hypothesize that changes in these pathways potentially lead to more protein catabolism and lean muscle mass loss and delayed wound healing, which could potentially explain the higher rate of skilled care disposition shown by females in this cohort.…”