LY2584702 Environmental oxygen levels affect tissue vascular

Environmental oxygen levels affect tissue vascularization and fracture healing. A previous study suggested that hyperoxia (50% O2 and 1ATA) increased tissue vascularization but did not significantly alter osteogenesis during the early stages of fracture healing (Lu et al., 2013). Most of the inspired atmospheric oxygen was carried by LY2584702 (Hb) and delivery to the fracture site. After Hb saturation, the oxygen level may not be high enough to increase the osteogenesis in the avascular fracture site. In this study, HBO (hyperbaric oxygen, a combination of 100% O2 and 2.5ATA) increased osteogenesis of bone healing. After Hb saturation, HBO may result in greater amounts of O2 dissolved in plasma to improve the environmental oxygen levels at the avascular fracture site than hyperoxia treatment only. The additive effects of increased pressure and increased O2 were demonstrated in this study. Long-term and repeated HBO treatments may increase oxidative stress (Korhonen et al., 1999); however, tolerance to HBO treatment can be extended by intermittent exposure. The authors used a clinical HBO protocol in this study. Because exposure to HBO in clinical protocols is rather brief (typically <2h/d), studies show that antioxidant defenses are adequate so that biochemical stresses related to increases in ROS are reversible (Korhonen et al., 1999).
Conclusions
Acknowledgments This research was supported in part by grants from the National Science Council and Chang Gung Memorial Hospital, Taiwan, Republic of China.
Introduction An open wound injury triggers a healing process that requires the well-orchestrated integration of complex biological and molecular events, and impairment of this process results in pathological conditions (Falanga, 2005; Martin, 1997; Singer and Clark, 1999). Despite advances in wound care, around 6.5 million patients suffer from pathological conditions and over 72,000 amputations occur each year in the United States alone (Brem et al., 2006). Current medical interventions, such as systemic (e.g. hyperbaric oxygen therapy) or topical (e.g. growth factor; PDGF) therapy, and mechanical devices for wound protection, attain only a 50% recovery, and fail in many cases to prevent chronic wound-related lower limb amputations. The cost of treatment is staggering, at $25 billion annually in the U.S., and the burden is rapidly growing (Sen et al., 2009). Inflammation is crucial to the normal wound healing process, however, persistent inflammation leads to impaired healing (Barone et al., 1998; Stadelmann et al., 1998; Trengove et al., 2000; Zhou et al., 2000). Several pro-inflammatory factors, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), were found in significantly higher concentrations in human (Tarnuzzer and Schultz, 1996; Trengove et al., 2000) and in murine (Zhou et al., 2000) wound fluid from non-healing leg ulcers compared to healing ulcers. Fibroblasts act as sentinel cells (Cooney et al., 1997) and it is evident that most of the pro-inflammatory factors are transcriptionally regulated by a nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB)-mediated pathway (Kleinert et al., 1996; Xie et al., 1994). Interleukin (IL)-10 is one of the most important anti-inflammatory molecules that acts to inhibit the production of pro-inflammatory cytokines (Wang et al., 1995) through the suppression of NF-κB activation and also promote regenerative healing in a cutaneous wound model (Peranteau et al., 2008). The activation and translocation of NF-κB to the nucleus is followed by transcription of iNOS (Kleinert et al., 1996) and pro-inflammatory cytokines (Baldwin, 1996; Ghosh and Karin, 2002). Previous studies have identified NF-κB transcription factors as key regulators of TNF-α -induced inflammatory gene expression in fibroblasts and other cellular systems (Kleinert et al., 1996; Xie et al., 1994). Thus inhibition of NF-κB activity can be a potential mechanism for regulating inflammatory responses. Studies indicate that IL-10 inhibits NF-κB activation upon TNF-α stimulation in various cell types (Dhingra et al., 2009; Wang et al., 1995).