Abstract Patients with sepsis have impaired host defenses that contribute to the lethality of disorder. Recent work implicates lymphocyte apoptosis as a potential factor in immunosuppression sepsis. If is an important mechanism, specific subsets lymphocytes may be more vulnerable. A prospective study cell typing and was conducted spleens from 27 patients 25 trauma. Spleens 16 critically ill nonseptic (3 13 retrospective) were also evaluated. Immunohistochemical staining showed...

Sepsis induces extensive lymphocyte apoptosis, a process which may be beneficial to host survival by down-regulating the inflammatory response or, alternatively, harmful impairing defenses. To determine vs. adverse effects of apoptosis in sepsis, we blocked either N- benzyloxycarbonyl-Val-Ala-Asp( O -methyl) fluoromethyl ketone ( z -VAD), broad-spectrum caspase inhibitor, or use Bcl-2 Ig transgenic mice that selectively overexpress antiapoptotic protein lymphoid pattern. Both -VAD and...

Abstract In sepsis there is extensive apoptosis of lymphocytes, which may be beneficial by down-regulating the accompanying inflammation. Alternatively, detrimental impairing host defense. We studied whether Bcl-2, a potent antiapoptotic protein, could prevent lymphocyte in clinically relevant model sepsis. Transgenic mice Bcl-2 was overexpressed T cells had complete protection against sepsis-induced thymus and spleen. Surprisingly, also decrease splenic B cell septic overexpressors compared...

Abstract Patients with sepsis are immune compromised, as evidenced by their failure to clear primary infection and propensity develop secondary infections pathogens that often not particularly virulent in normal healthy individuals. A potential mechanism for immunosuppression is lymphocyte apoptosis, which may occur either a death receptor or mitochondrial-mediated pathway. prospective study of blood samples from 71 patients sepsis, 55 nonseptic patients, 6 volunteers was undertaken...

IL-15 is a pluripotent antiapoptotic cytokine that signals to cells of both the innate and adaptive immune system regarded as highly promising immunomodulatory agent in cancer therapy. Sepsis lethal condition which apoptosis-induced depletion subsequent immunosuppression are thought contribute morbidity mortality. This study tested ability block apoptosis, prevent immunosuppression, improve survival sepsis. Mice were made septic using cecal ligation puncture or Pseudomonas aeruginosa...

In sepsis, both necrotic and apoptotic cell death can occur. Apoptotic cells induce anergy that could impair the host response, whereas cause immune activation might result in enhanced antimicrobial defenses. We determined whether adoptive transfer of or impacted survival a clinically relevant sepsis model. also evaluated effects on prototypical TH1 TH2 cytokines IFN-γ IL-4, respectively. C57BL6/J mice had (irradiated) (freeze thaw) splenocytes. Controls received saline. greatly increased...

Abstract Dendritic cells are a phenotypically diverse group of APC that have unique capabilities to regulate the activity and survival B T cells. Although proper function dendritic is essential host control invading pathogens, few studies examined impact sepsis on The purpose this study was determine effect splenic interdigitating (IDCs) follicular (FDCs) using clinically relevant animal model. Immunohistochemical staining for FDCs showed induced an initial marked expansion in peaked at 36 h...

Abstract Sepsis induces extensive death of lymphocytes that may contribute to the immunosuppression and mortality disorder. The serine/threonine kinase Akt is a key regulator cell proliferation death. purpose this study was determine whether overexpression would prevent lymphocyte apoptosis improve survival in sepsis. In addition, given important role signaling, T Th1 Th2 cytokine production determined. Mice overexpress constitutively active were made septic, recorded. Lymphocyte determined...

Abstract Sepsis induces widespread lymphocyte apoptosis, resulting in impaired immune defenses and increased morbidity mortality. There are multiple potential triggers or signaling molecules involved mediating death signals. Elucidating the specific pathways that apoptosis may lead to improved therapies of this lethal disorder. We investigated a number key cellular receptors intracellular be responsible for apoptotic cell death. Specifically, we role pathogen-associated molecular patterns...

Immunomodulation of mast cell (MC) activity is warranted in allergic and inflammatory diseases where MCs have a central role pathogenesis. Targeting Siglec-8, an inhibitory receptor on eosinophils, has shown promising preclinical clinical studies. While the intracellular pathways that regulate Siglec-8 eosinophils been well studied, signaling mechanisms lead to MC inhibition not fully elucidated. Here, we evaluate Siglec-8-mediated primary using anti-Siglec-8 monoclonal antibody (mAb)....

The mechanism(s) that increase retinal and visual cortex blood flows in response to stimulation are poorly understood. We tested the hypothesis increased transfer of electrons protons from glucose cytosolic free NAD(+), reducing it NADH, evoked by energy metabolism, fuels redox-signaling pathways augment flow. near-equilibrium between NADH/NAD(+) lactate/pyruvate ratios established lactate dehydrogenase predicts additional injected NAD(+) will elevated stimulated retina cortex, whereas NADH...

Whereas most septic patients have an underlying comorbidity, animal models of sepsis use mice that were healthy before the onset infection. Malignancy is common comorbidity associated with sepsis. The purpose this study was to determine whether cancer a different response than animals.Prospective, randomized controlled study.Animal laboratory in university medical center.C57Bl/6 mice.Animals received subcutaneous injection either 250,000 cells transplantable pancreatic adenocarcinoma cell...

This study examined the fate of dendritic cells (DCs) and macrophages (MΦ) in vivo a murine model sepsis. Wild-type, knockout, transgenic mice were used to examine role Bcl-2 family members on regulation splenic DCs MΦ survival. Bim knockout (Bim−/−) overexpressing selected hematopoietic used: (a) overexpression all using vav promoter (Vav-Bcl-2) (b) Major histocompatibility complex (MHC) class I (H-2K-Bcl-2). Mice underwent sham surgery or cecal ligation puncture, absolute numbers...

Abstract Mast cells (MC) are key drivers of allergic and inflammatory diseases. Sialic acid-binding immunoglobulin-like lectin (Siglec)-6 is an immunoregulatory receptor found on MCs. While it recognized that engaging Siglecs with antibodies mediates inhibition across immune cells, the mechanisms govern this agonism not understood. Here we generated Siglec-6 mAb clones (AK01 to AK18) better understand Siglec-6-mediated agonism. mAbs displayed epitope-dependent internalization inhibitory...

Abstract Background Sialic acid‐binding immunoglobulin‐like lectin (Siglec)‐6 and Siglec‐8 are closely related mast cell (MC) receptors with broad inhibitory activity, but whose functional differences incompletely understood. Methods Proteomic profiling using quantitative mass spectrometry was performed on primary mouse MCs to identify proteins associated Siglec‐6 Siglec‐8. For characterization, each receptor evaluated biochemically in ex vivo inhibition models of IgE non‐IgE‐mediated MC...

Lymphocytes help determine whether gut epithelial cells proliferate or differentiate but are not known to affect they live die. Here, we report that lymphocytes play a controlling role in mediating apoptosis sepsis under basal conditions. Gut is similar unmanipulated Rag-1(-/-) and wild-type (WT) mice. However, animals have 5-fold augmentation following cecal ligation puncture (CLP) compared septic WT Reconstitution of mice via adoptive transfer decreases intestinal levels seen animals....

Abstract Lymphocyte apoptosis is thought to have a major role in the pathophysiology of sepsis. However, there disconnect between animal models sepsis and patients with disease, because former use subjects that were healthy prior onset infection while most underlying comorbidities. The purpose this study was determine whether lymphocyte prevention effective preventing mortality septic mice preexisting cancer. Mice Bcl-2 overexpression (Bcl-2-Ig) wild type (WT) injected transplantable...

We hypothesized that spleen microarray gene expression profiles analyzed with contemporary pathway analysis software would provide molecular pathways of interest and target genes might help explain the effect bcl-2 on improving survival during sepsis. Two mouse models sepsis, cecal ligation puncture tracheal instillation Pseudomonas aeruginosa, were tested in both wild-type mice overexpress bcl-2. Whole spleens obtained 6 h after septic injury. DNA transcriptional using Affymetrix 430A...

INTRODUCTION: The pathophysiology of AAAs is multifactorial, involving chronic inflammation, increased MMP expression/activity, and medial elastic fiber destruction. RAGE transduces the biological impact ligand families including AGEs, S100, HMGB1 to upregulate inflammatory tissue injury-provoking genes MMPs. We previously identified expression in human have shown that absence RAGE, whether by genetic deletion or pharmacologic blockade with sRAGE, prevents AAA formation a mouse model. sought...

<h3>Background</h3> Myeloid cells are the most abundant immune within tumor microenvironment (TME) where they play important roles regulating anti-tumor immunity. Targeting myeloid-specific inhibitory receptors to modulate TME represents an attractive strategy improve therapeutic outcome of current cancer therapies. Siglec-10 is receptor expressed on tumor-associated macrophages (TAMs) and dendritic that regulates cell activation via immunoreceptor tyrosine-based motifs. Recently, was shown...