Bacterial sepsis triggers an antiviral response that causes translation shutdown.

In response to viral pathogens, the host upregulates antiviral genes that suppress translation of viral mRNAs. However, induction of such antiviral responses may not be exclusive to viruses, as the pathways lie at the intersection of broad inflammatory networks that can also be induced by bacterial pathogens. Using a model of Gram-negative sepsis, we show that propagation of kidney damage initiated by a bacterial origin ultimately involves antiviral responses that result in host translation shutdown.

Endotoxin Preconditioning Reprograms S1 Tubules and Macrophages to Protect the Kidney.

Preconditioning with a low dose of endotoxin confers unparalleled protection against otherwise lethal models of sepsis. The mechanisms of preconditioning have been investigated extensively in isolated immune cells such as macrophages. However, the role of tissue in mediating the protective response generated by preconditioning remains unknown.

Inhibition of Toll-Like Receptor 4 Signaling Mitigates Microvascular Loss but Not Fibrosis in a Model of Ischemic Acute Kidney Injury.

The development of chronic kidney disease (CKD) following an episode of acute kidney injury (AKI) is an increasingly recognized clinical problem. Inhibition of toll-like receptor 4 (TLR4) protects renal function in animal models of AKI and has become a viable therapeutic strategy in AKI. However, the impact of TLR4 inhibition on the chronic sequelae of AKI is unknown.

Novel application of complementary imaging techniques to examine in vivo glucose metabolism in the kidney.

The metabolic status of the kidney is a determinant of injury susceptibility and a measure of progression for many disease processes; however, noninvasive modalities to assess kidney metabolism are lacking. In this study, we employed positron emission tomography (PET) and intravital multiphoton microscopy (MPM) to assess cortical and proximal tubule glucose tracer uptake, respectively, following experimental perturbations of kidney metabolism. Applying dynamic image acquisition PET with 2-fluoro-2-deoxyglucose (F-FDG) and tracer kinetic modeling, we found that an intracellular compartment in the cortex of the kidney could be distinguished from the blood and urine compartments in animals.

The macrophage mediates the renoprotective effects of endotoxin preconditioning.

Preconditioning is a preventative approach, whereby minimized insults generate protection against subsequent larger exposures to the same or even different insults. In immune cells, endotoxin preconditioning downregulates the inflammatory response and yet, preserves the ability to contain infections. However, the protective mechanisms of preconditioning at the tissue level in organs such as the kidney remain poorly understood.

p53 is renoprotective after ischemic kidney injury by reducing inflammation.

In the rat, p53 promotes tubular apoptosis after ischemic AKI. Acute pharmacologic inhibition of p53 is protective in this setting, but chronic inhibition enhances fibrosis, demonstrating that the role of p53 in ischemic AKI is incompletely understood. Here, we investigated whether genetic absence of p53 is also protective in ischemic AKI.

The p53 inhibitor pifithrin-α can stimulate fibrosis in a rat model of ischemic acute kidney injury.

Inhibition of the tumor suppressor p53 diminishes tubular cell apoptosis and protects renal function in animal models of acute kidney injury (AKI). Therefore, targeting p53 has become an attractive therapeutic strategy in the approach to AKI. Although the acute protective effects of p53 inhibition in AKI have been examined, there is still relatively little known regarding the impact of acute p53 inhibition on the chronic sequelae of AKI.

Endotoxin uptake by S1 proximal tubular segment causes oxidative stress in the downstream S2 segment.

Gram-negative sepsis carries high morbidity and mortality, especially when complicated by acute kidney injury (AKI). The mechanisms of AKI in sepsis remain poorly understood. Here we used intravital two-photon fluorescence microscopy to investigate the possibility of direct interactions between filtered endotoxin and tubular cells as a possible mechanism of AKI in sepsis.

p53 regulates renal expression of HIF-1{alpha} and pVHL under physiological conditions and after ischemia-reperfusion injury.

Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI) and is characterized by widespread tubular and microvascular damage. The tumor suppressor p53 is upregulated after IRI and contributes to renal injury in part by promoting apoptosis. Acute, short-term inhibition of p53 with pifithrin-alpha conveys significant protection after IRI.

Sepsis induces an increase in thick ascending limb Cox-2 that is TLR4 dependent.

Cyclooxygenase-2 (Cox-2) is an inducible enzyme responsible for the formation of inflammatory prostanoids such as prostaglandins and thromboxane. Its role in the pathophysiology of inflammatory states like sepsis is increasingly recognized. Recently, we demonstrated that sepsis upregulates the endotoxin receptor Toll-like receptor 4 (TLR4) in rat kidney.

Sepsis induces changes in the expression and distribution of Toll-like receptor 4 in the rat kidney.

Toll-like receptors (TLRs) are now recognized as the major receptors for microbial pathogens on cells of the innate immune system. Recently, TLRs were also identified in many organs including the kidney. However, the cellular distribution and role of these renal TLRs remain largely unknown.

Minocycline reduces renal microvascular leakage in a rat model of ischemic renal injury.

Tetracyclines exhibit significant anti-inflammatory properties, inhibit matrix metalloproteinases (MMPs), and are protective in models of ischemia-reperfusion injury (IRI). Both inflammatory cascades and MMP activation have been demonstrated to modulate microvascular permeability. Because increased microvascular permeability occurs during IRI in a variety of organ systems including the kidney, we hypothesized that minocycline, a semisynthetic tetracycline, would diminish microvascular leakage during renal IRI.

Minocycline inhibits apoptosis and inflammation in a rat model of ischemic renal injury.

Tetracyclines exhibit significant anti-inflammatory properties in a variety of rheumatologic and dermatologic conditions. They have also been shown to inhibit apoptosis in certain neurodegenerative disorders. Because ischemic renal injury is characterized by both apoptosis and inflammation, we investigated the therapeutic potential of tetracyclines in a rat model of renal ischemia-reperfusion.

P53 mediates the apoptotic response to GTP depletion after renal ischemia-reperfusion: protective role of a p53 inhibitor.

Ischemic injury to the kidney is characterized in part by nucleotide depletion and tubular cell death in the form of necrosis or apoptosis. GTP depletion was recently identified as an important inducer of apoptosis during chemical anoxia in vitro and ischemic injury in vivo. It has also been shown that GTP salvage with guanosine prevented apoptosis and protected function.

Guanine nucleosides and Jurkat cell death: roles of ATP depletion and accumulation of deoxyribonucleotides.

Guanine nucleosides are toxic to some forms of cancer. This toxicity is pronounced in cancers with upregulated guanine nucleotide synthesis, but the mechanisms are poorly understood. We investigated this toxicity by measuring the effects of guanine nucleosides on nucleotides in Jurkat cells using HPLC.

Guanosine supplementation reduces apoptosis and protects renal function in the setting of ischemic injury.

Ischemic injury to the kidney is characterized in part by nucleotide depletion and tubular cell death in the form of necrosis or apoptosis. Recently, we linked anoxia-induced apoptosis in renal cell cultures specifically to the depletion of GTP. We therefore hypothesized that enhancing GTP repletion in vivo might protect function by reducing apoptosis in postischemic tubules.

Synergistic cytotoxic effect of interferon-gamma and tumor necrosis factor-alpha on cultured human muscle cells.

Objective: To investigate the effects of human interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha), either alone or in combination, on the viability of human muscle cells in culture.

Methods: Cultures of human muscle cells were treated with various concentrations of recombinant IFN-gamma and TNF-alpha alone and in combination, and the cytotoxic effects of the cytokines on muscle cells were assessed by measuring lactic dehydrogenase (LDH) release in supernatants and by observation of the cells for morphologic changes under phase microscopy.

Results: Exposure of muscle cells to 100 U/ml of either IFN-gamma or TNF-alpha for 9 days caused no cytotoxic effects, as assessed by LDH release in supernatants of muscle cell cultures and by microscopic observation of the cell cultures.

The role of cytokines in polymyositis. III. Recombinant human interferon-gamma enhances T cell adhesion to cultured human muscle cells.

Objective: To investigate the effect of interferon-gamma (IFN gamma) on the adhesive interactions between human peripheral blood T cells and human skeletal muscle cells at various stages of muscle cell differentiation and maturation in vitro.

Methods: Human muscle cell cultures were established from normal muscle biopsy material, using the explant technique. T cells were studied for their capacity to adhere to IFN gamma-treated and untreated myoblasts and myotubes.

Interferon-gamma inhibits proliferation, differentiation, and creatine kinase activity of cultured human muscle cells. II. A possible role in myositis.

Objective: To investigate the effects of human interferon-gamma (IFN-gamma) on cultured human skeletal muscle cells.

Methods: Muscle cell cultures were treated with various concentrations of recombinant human IFN-gamma, and muscle cell proliferation, creatine kinase synthesis and muscle cell cytotoxicity were analyzed.

Results: Treatment of muscle cell cultures with IFN-gamma resulted in significant inhibition of myoblasts proliferation, growth, and fusion into multinucleated myotubes.

Proliferative response of peripheral blood mononuclear cells to autologous and allogeneic muscle in patients with polymyositis/dermatomyositis.

We examined the proliferative responses of peripheral blood mononuclear cells (PBMC) to autologous and homologous muscle homogenates in 21 patients with early, active, untreated polymyositis/dermatomyositis (PM/DM), 8 patients with chronic PM/DM, 10 patients with myopathies other than PM/DM, 7 patients with connective tissue diseases without myositis, and 12 healthy individuals. PBMC from patients with PM/DM and from control subjects were incubated with various dilutions of autologous and homologous muscle homogenates. PBMC from patients with active PM/DM underwent significant proliferation on exposure to both the autologous muscle and the homologous muscle homogenates.