No abstract

Subclinical levels of circulating endotoxin are associated with the pathogenesis of diverse human inflammatory diseases, by mildly inducing the expression of proinflammatory mediators. In this study, we examined the molecular mechanism responsible for the effect of low-dose LPS in macrophages. In contrast to high-dose LPS, which activates NF-κB and induces the robust expression of proinflammatory mediators, we observed that low-dose LPS failed to activate NF-κB. Instead, it selectively activated C/EBPδ and removed nuclear repressors, including peroxisome proliferator-activated receptor α and retinoic acid receptor α, enabling a mild and leaky expression of proinflammatory mediators. The effect of low-dose LPS required IRAK-1, which interacts with and acts upstream of IκB kinase ε to contribute to LPS-mediated induction of C/EBPδ and proinflammatory mediators. Additionally, mice fed a high-fat diet acquired elevated levels of endotoxin and proinflammatory mediators in an IRAK-1–dependent fashion. Taken together, these data reveal a distinct pathway preferentially used by low-dose endotoxin in initiating low-grade inflammation.

Although both inflammatory and metabolic complications occur during sepsis and endotoxemia, relatively few studies have examined the molecular mechanism underlying LPS-modulated metabolic changes during sepsis. In this report, we have demonstrated that LPS suppresses free fatty acid (FFA) oxidation, and consequently contributes to elevated plasma levels of FFA and triglyceride (TG). Furthermore, this process depends upon the interleukin-1 receptor associated kinase 1 (IRAK-1), one of the key TLR4 intracellular signaling kinases. IRAK-1 −/− mice fail to exhibit the dramatic rise in plasma FFA and TG levels compared to wild type (WT) mice following lethal LPS injection. Mechanistically, we demonstrated that LPS suppresses FFA oxidation through decreasing the expression levels of key FFA oxidative genes including CPT-1 and MCAD in both liver and kidney tissues of WT but not IRAK-1 −/− mice. The expression of CPT-1 and MCAD is controlled by nuclear receptors and co-receptors including PPARα and PGC-1α. We observed that LPS selectively suppresses the levels of PPARα and PGC-1α in tissues from WT, but not IRAK-1 −/− mice. Consequently, IRAK-1 −/− mice have a higher survival rate following a lethal dose of LPS. Our current study reveals a novel role for IRAK-1 in the metabolic alterations induced by LPS.

Increasing clinical observations reveal that persistent low-grade inflammation is associated with the pathogenesis of severe chronic diseases such as atherosclerosis, diabetes, and aging-related neurological diseases. Intriguingly, low levels of circulating Gram-negative bacterial endotoxin lipopolysaccharide (LPS) appear to be one of the key culprits in provoking a non-resolving low-grade inflammation. Adverse life styles, chronic infection, and aging can all contribute to the rise of circulating endotoxin levels and lead to low-grade endotoxemia. As a consequence, low-grade endotoxemia may skew host immune environment into a mild non-resolving pro-inflammatory state, which eventually leads to the pathogenesis and progression of inflammatory diseases. This review aims to highlight the recent progress in the causes and consequences of low-grade endotoxemia, as well as the emerging molecular mechanisms responsible.

We present a passive (unpowered) exoskeleton that assists the back during lifting. Our exoskeleton uses carbon fiber beams as the sole means to store energy and return it to the wearer. To motivate the design, we present general requirements for the design of a lifting exoskeleton, including calculating the required torque to support the torso for people of different weights and heights. We compare a number of methods of energy storage for exoskeletons in terms of mass, volume, hysteresis, and cycle life. We then discuss the design of our exoskeleton, and show how the torso assembly leads to balanced forces. We characterize the energy storage in the exoskeleton and the torque it provides during testing with human subjects. Ten participants performed freestyle, stoop, and squat lifts. Custom image processing software was used to extract the curvature of the carbon fiber beams in the exoskeleton to determine the stored energy. During freestyle lifting, it stores an average of 59.3 J and provides a peak torque of 71.7 Nm.