Bacterial endotoxin [lipopolysaccharide (LPS)] stimulates macrophages to sequentially release early [tumor necrosis factor (TNF)] and late [high mobility group box 1 (HMGB1)] proinflammatory cytokines. The requirement of CD14 and mitogen-activated protein kinases [MAPK; e.g., p38 and extracellular signal-regulated kinase (ERK)1/2] for endotoxin-induced TNF production has been demonstrated previously, but little is known about their involvement in endotoxin-mediated HMGB1 release. Here, we demonstrated that genetic disruption of CD14 expression abrogated LPS-induced TNF production but only partially attenuated LPS-induced HMGB1 release in cultures of primary murine peritoneal macrophages. Pharmacological suppression of p38 or ERK1/2 MAPK with specific inhibitors (SB203580, SB202190, U0126, or PD98059) significantly attenuated LPS-induced TNF production but failed to inhibit LPS-induced HMGB1 release. Consistently, an endogenous, immunosuppressive molecule, spermine, failed to inhibit LPS-induced activation of p38 MAPK and yet, still significantly attenuated LPS-mediated HMGB1 release. Direct suppression of TNF activity with neutralizing antibodies or genetic disruption of TNF expression partially attenuated HMGB1 release from macrophages induced by LPS at lower concentrations (e.g., 10 ng/ml). Taken together, these data suggest that LPS stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms.

To defi ne the roles of endothelial-intrinsic nuclear factor B (NF-B) activity in host defense and multiple organ injury in response to sepsis, we generated double transgenic (TG) mice (EC-rtTA/I-B ␣ mt) that conditionally overexpress a degradation-resistant form of the NF-B inhibitor I-B ␣ (I-B ␣ mt) selectively on vascular endothelium. The ECrtTA/I-B ␣ mt mice had no basal, but a relatively high level of doxycycline-inducible, I-B ␣ mt expression. I-B ␣ mt expression was detected in endothelial cells, but not in fi broblasts, macrophages, and whole blood cells, confi rming that transgene expression was restricted to the endothelium. When subjected to endotoxemia, EC-rtTA/I-B ␣ mt mice showed endothelial-selective blockade of NF-B activation, repressed expression of multiple endothelial adhesion molecules, reduced neutrophil infi ltration into multiple organs, decreased endothelial permeability, ameliorated multiple organ injury, reduced systemic hypotension, and abrogated intravascular coagulation. When subjected to cecal ligation and puncture -induced sepsis, the TG mice had less severe multiple organ injury and improved survival compared with wild-type (WT) mice. WT and EC-rtTA/I-B ␣ mt mice had comparable capacity to clear three different pathogenic bacteria. Our data demonstrate that endothelial NF-B activity is an essential mediator of septic multiple organ infl ammation and injury but plays little role in the host defense response to eradicate invading pathogenic bacteria.

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The proinflammatory factor high-mobility group box protein 1 (HMGB1) has been implicated in the pathogenesis of lung fibrosis; however, the role of HMGB1 in lung fibrosis remains unclear. It has previously been reported that nuclear factor (NF)-κB and transforming growth factor (TGF)-β1 may be involved in lung fibrosis. Therefore, the present study aimed to examine the potential molecular mechanisms that underlie HMGB1-induced lung fibrosis via the regulation of NF-κB and TGF-β1. The results demonstrated that HMGB1 stimulation increased the activation of NF-κB and the release of TGF-β1, as well as the expression of α-smooth muscle actin (α-SMA) and collagen I in human lung fibroblasts in vitro. In addition, inhibition of NF-κB activation blocked HMGB1-induced TGF-β1 release, as well as α-SMA and collagen I expression in lung fibroblasts. Preventing the release of TGF-β1 inhibited HMGB1-induced α-SMA and collagen I expression; however, it had no effect on NF-κB activation. Collectively, these findings indicate that HMGB1 induces fibroblast to myofibroblast differentiation of lung fibroblasts via NF-κB-mediated TGF-β1 release.

Summary Background The biological mechanisms underlying the use of platelet‐rich plasma (PRP), as well as the efficacy and possible adverse effects of PRP, have not yet been fully elucidated. Prior studies have evaluated PRP for cutaneous ulceration. However, the benefits from PRP still remain controversial and few have assessed the effects of ulceration etiologies. The purpose of our study is to determine the efficacy and safety of PRP and which kind of ulcer is more suitable for PRP by analyzing the effects of PRP on ulcers with different causes. Methods A comprehensive search was performed to identify randomized controlled trials (RCTs) regarding the application of PRP from PubMed, EMBASE, Scopus, and the Cochrane Library. The data were analyzed using Review Manager 5.3. Results A total of nineteen RCTs (909 patients) were included. In contrast with conventional treatments, PRP achieved higher healing rate, higher percentage of area reduction, and smaller final area in vascular ulcers. However, the advantage disappeared in diabetic and pressure ulcers. Concerning adverse events, PRP showed lower incidence in the short term, but higher in the long term. No significant differences were found in ulcer closure velocity and healing time. Conclusion Platelet‐rich plasma effectiveness and safety in treating cutaneous ulceration depend on what is the ulceration etiology. For diabetic ulcers, PRP showed no satisfactory results suggesting that PRP may not be suitable for diabetic patients. However, PRP could be efficient and more beneficial for vascular ulcers and effects on pressure ulcers remain unclear. Thus, PRP option should be carefully considered for each patient in accordance with their ulceration etiologies.

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