Contrary to previous dogmas, it is now well established that brain cells can produce cytokines and chemokines, and can express adhesion molecules that enable an in situ inflammatory reaction. The accumulation of neutrophils early after brain injury is believed to contribute to the degree of brain tissue loss. Support for this hypothesis has been drawn from many studies where neutrophil-depletion blockade of endothelial-leukocyte interactions has been achieved by various techniques. The inflammation reaction is an attractive pharmacologic opportunity, considering its rapid initiation and progression over many hours after stroke and its contribution to evolution of tissue injury. While the expression of inflammatory cytokines that may contribute to ischemic injury has been repeatedly demonstrated, cytokines may also provide "neuroprotection" in certain conditions by promoting growth, repair, and ultimately, enhanced functional recovery. Significant additional basic work is required to understand the dynamic, complex, and time-dependent destructive and protective processes associated with inflammation mediators produced after brain injury. The realization that brain ischemia and trauma elicit robust inflammation in the brain provides fertile ground for discovery of novel therapeutic agents for stroke and neurotrauma. Inhibition of the mitogen-activated protein kinase (MAPK) cascade via cytokine suppressive anti-inflammatory drugs, which block p38 MAPK and hence the production of interleukin-1 and tumor necrosis factor-alpha, are most promising new opportunities. However, spatial and temporal considerations need to be exercised to elucidate the best opportunities for selective inhibitors for specific inflammatory mediators.

https://journals.sagepub.com/doi/pdf/10.1097/00004647-199908000-00001

Inflammatory mediators and stroke: new opportunities for novel therapeutics.

The role of inflammation and cytokines in brain injury

Despite the wide success of antibiotics, the treatment of bacterial infections still faces significant challenges, particularly the emergence of antibiotic resistance. As a result, nanoparticle drug delivery platforms including liposomes, polymeric nanoparticles, dendrimers, and various inorganic nanoparticles have been increasingly exploited to enhance the therapeutic effectiveness of existing antibiotics. This review focuses on areas where nanoparticle approaches hold significant potential to advance the treatment of bacterial infections. These areas include targeted antibiotic delivery, environmentally responsive antibiotic delivery, combinatorial antibiotic delivery, nanoparticle-enabled antibacterial vaccination, and nanoparticle-based bacterial detection. In each area we highlight the innovative antimicrobial nanoparticle platforms and review their progress made against bacterial infections.

/pdf/nanoparticle-approaches-against-bacterial-infections-56irc0uk6a.pdf

Nanoparticle approaches against bacterial infections.

T cells seem to be responsible for liver damage in any type of acute hepatitis. Nevertheless, the importance of Kupffer cells (KCs) for T-cell-dependent liver failure is unclear. Here we focus on the role of KCs and tumor necrosis factor (TNF) production after T cell stimulation in mice. T-cell- and TNF-dependent liver injury were induced either by Pseudomonas exotoxin A (PEA), by concanavalin A (Con A), or by the combination of subtoxic doses of PEA and the superantigen Staphylococcus enterotoxin B (SEB). KCs were depleted by clodronate liposomes. Although livers of PEA-treated mice contained foci of confluent necrosis and numerous apoptotic cells, hardly any apoptotic cells were observed in the livers of Con A-treated mice. Instead, large bridging necroses were visible. Elimination of KCs protected mice from PEA-, Con A-, or PEA/SEB-induced liver injury. In the absence of KCs, liver damage was restricted to a few small necrotic areas. KCs were the main source of TNF. Hepatic TNF mRNA and protein production were strongly attenuated because of KC-depletion whereas plasma TNF levels were unaltered. Our results suggest that KCs play an important role in T cell activation-induced liver injury by contributing TNF. Plasma TNF levels are poor diagnostic markers for the severity of TNF-dependent liver inflammation.

/pdf/importance-of-kupffer-cells-for-t-cell-dependent-liver-21owyjmbnh.pdf

Importance of Kupffer cells for T-cell-dependent liver injury in mice.

Accumulating evidence during the last decade has shown that the CNS can mount a well-defined inflammatory reaction to a variety of insults including trauma, ischemia, transplantation, viral infections

The role of cytokines in the neuropathology of stroke and neurotrauma.

Protein kinase c inhibitors suppress lps-induced tnf production in alveolar macrophages and in whole blood : the role of encapsulation into liposomes

Effects of liposome-encapsulated dichloromethylene diphosphonate on macrophage function and endotoxin-induced mortality.

Bacterial lipopolysaccharide (LPS) can elicit septic shock; however, there is growing evidence that most of its pathophysiological effects are mediated by the release of tumor necrosis factor (TNF) and other cytokines. In turn, LPS-induced TNF production is thought to implicate the activation of intracellular protein kinase C (PKC). In this study, we examined whether pH-sensitive liposomes containing staurosporine (STP), a potent inhibitor of PKC, when injected intravenously would suppress TNF production and reduce mortality in an endotoxin rat model. We found that pretreatment of rats with pH-sensitive STP-liposomes by intravenous administration 1.5 h prior to LPS injection decreased lethality from 80% to approximately 30%. Importantly, this improvement in outcome was associated with significant reductions in TNF serum levels; 1 h after LPS injection serum TNF was 73% lower than in a saline control group, and at 2 h TNF levels were 84% lower. STP-liposome pretreatment also ameliorated the severe reduction in body temperature, characteristic for a hypodynamic shock, that was observed in LPS-challenged rats, but had relatively little effect on the transient leukopenia. We conclude that STP-liposomes can suppress LPS-induced TNF production by the mononuclear phagocytic system, can reduce the symptoms of septic shock, and can increase survival.

Staurosporine encapsulated into pH-sensitive liposomes reduces tnf production and increases survival in rat endotoxin shock.

1 The synthesis of nitric oxide (NO) by immune‐stimulated murine phagocytic cells (J774) and the modulation of this synthesis by tricyclodecan‐9‐yl‐xanthogenate (D609), a specific inhibitor of phosphatidylcholine‐specific phospholipase C (PC‐PLC), was investigated. D609 dose‐dependently suppressed production of NO, as measured by the release of nitrite and nitrate, in response to lipopolysac‐charide (LPS) and interferon‐γ (IFN‐γ) in intact cultured cells with an IC50 of approximately 20 μg ml−1. D609 at 40 μg ml−1 completely abrogated immune‐stimulated nitrite production. 2 The inhibitory effects of D609 on nitrite production were time‐dependent and restricted to the first 18 h post‐stimulation. D609 did not inhibit nitrite production in the cytosol of immune‐stimulated phagocytes. 3 These findings indicate that the xanthogenate, D609, is a potent inhibitor of the induction of NO‐synthase activity in immune‐stimulated phagocytes. Furthermore, since D609 has been demonstrated to inhibit PC‐PLC specifically, our findings suggest that the activation of this enzyme by LPS and IFN‐γ is a proximal step in the signal transduction of inducible NO‐synthase in phagocytic cells.

Induction ofnitric oxide synthase activity inphagocytic cells inhibited bytricyclodecan-9- yl-xanthogenate (D609)

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Protein kinase c inhibitors suppress lps-induced tnf production in alveolar macrophages and in whole blood : the role of encapsulation into liposomes

Effects of liposome-encapsulated dichloromethylene diphosphonate on macrophage function and endotoxin-induced mortality.

Staurosporine encapsulated into pH-sensitive liposomes reduces tnf production and increases survival in rat endotoxin shock.

Induction ofnitric oxide synthase activity inphagocytic cells inhibited bytricyclodecan-9- yl-xanthogenate (D609)