Ethanol Feeding Inhibits Proinflammatory Cytokine Expression from Murine Alveolar Macrophages Ex Vivo

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66427/1/j.1530-0277.1997.tb04440.x.pd

Anti-tumor necrosis factor-alpha therapy during murine Klebsiella pneumoniae bacteremia: increased mortality in the absence of liver injury.

Klebsiella pneumoniae is a leading cause of gram-negative bacterial pneumonia, often resulting in bacteremia concurrent with the localized pulmonary infection. The beneficial role of tumor necrosis factor (TNF)-alpha during pulmonary infection has been well documented; however, consequences of TNF-alpha production during systemic bacterial infection are controversial. A murine model of K. pneumoniae was developed to address this important issue. Liver-associated TNF-alpha mRNA was induced within 30 min after intravenous bacterial inoculation and remained elevated through 6 h before returning to near-baseline at 24 h postinfection. Intravenous K. pneumoniae infection induced liver cellular injury that was completely ablated when mice were pretreated with a neutralizing anti-TNF-alpha antibody. Interestingly, this reduction in liver injury failed to translate into improved survival. Mice receiving anti-TNF-alpha continued to succumb to the infection even out to day 10 postinfection. Bacterial clearance after TNF-alpha neutralization was significantly impaired at later time points during infection. Correlating with impaired bacterial clearance was diminished production of liver-associated MIP-2, MIP-1alpha, MCP-1, and interferon-gamma. Further evidence of diminished antibacterial immune responses was noted when the activational status of splenic natural killer cells in anti-TNF-alpha-treated mice was examined 24 h postinfection. Natural killer cells displayed decreased CD69 expression. Combined, these data indicate that the beneficial effects of TNF-alpha during systemic K. pneumoniae infection outweigh the detrimental effects of TNF-alpha-mediated hepatocyte cellular injury. Anti-TNF-alpha therapy, although preventing liver injury during blood-borne bacterial infection, results in a dampened anti-bacterial host response, resulting in decreased bacterial clearance and overall survival

PPARs in Alveolar Macrophage Biology

PPARs, most notably PPAR-γ, play a crucial role in regulating the activation of alveolar macrophages, which in turn occupy a pivotal place in the immune response to pathogens and particulates drawn in with inspired air. In this review, we describe the dual role of the alveolar macrophage as both a first-line defender through its phagocytotic activity and a regulator of the immune response. Depending on its state of activation, the alveolar macrophage may either enhance or suppress different aspects of immune function in the lung. We then review the role of PPAR-γ and its ligands in deactivating alveolar macrophages—thus limiting the inflammatory response that, if unchecked, could threaten the essential respiratory function of the alveolus—while upregulating the cell's phagocytotic activity. Finally, we examine the role that inadequate or inappropriate PPAR-γ responses play in specific lung diseases

Sepsis and Nosocomial Infection: Patient Characteristics, Mechanisms, and Modulation

Sepsis is a leading cause of death worldwide. After initial trials modulating the hyperinflammatory phase of sepsis failed, generations of researchers have focused on evaluating hypo-inflammatory immune phenotypes. The main goal has been to develop prognostic biomarkers and therapies to reduce organ dysfunction, nosocomial infection, and death. The depressed host defense in sepsis has been characterized by broad cellular reprogramming including lymphocyte exhaustion, apoptosis, and depressed cytokine responses. Despite major advances in this field, our understanding of the dynamics of the septic host response and the balance of inflammatory and anti-inflammatory cellular programs remains limited. This review aims to summarize the epidemiology of nosocomial infections and characteristic immune responses associated with sepsis, as well as immunostimulatory therapies currently under clinical investigation

Mononuclear Cell Adherence Induces Neutrophil Chemotactic Factor/Interleukin‐8 Gene Expression

The accumulation of polymorphonuclear cells (PMN) in tissue is an essential element of the inflammatory response that is important in host defense. Adherence to endothelium constitutes the first step in PMN migration from the vascular compartment to the interstitium. We demonstrate that human peripheral blood mononuclear cells (PBMC) adherent to plastic can result in expression of interleukin‐8 (IL‐8), a potent PMN chemoattractant and activating cytokine. Northern blot analyses showed PBMC adherent to plastic expressed IL‐8 steady‐state mRNA levels by 30 min, peaked at 8 h, and then decreased over the next 16 h. In contrast, nonadherent PBMC (cultured in teflon chambers) expressed less than 25% of the maximal IL‐8 steady‐state mRNA levels as compared with adherent PBMC. Adherent PBMC‐associated IL‐8 determined by immunohistochemistry, supernatant chemotactic bioactivity, and extracellular antigenic IL‐8 paralleled IL‐8 mRNA expression. Antigenic and bioactive IL‐8 were significantly apparent by 4–8 h, respectively, and increased significantly to maximal levels by 24 h. Furthermore, adherent PBMC IL‐8 gene expression was suppressed by either concomitant treatment with actinomycin‐D or cycloheximide, yet specific neutralizing antibodies directed against either IL‐1β or tumor necrosis factor (TNF)‐α failed to alter adherence‐induced steady‐state IL‐8 mRNA levels. These data support the hypothesis that PBMC adherence is an important signal for the production of IL‐8, and may be essential to the development of the inflammatory response through the elicrtation of PMN.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141636/1/jlb0287.pd

Cooperative Interactions between TLR4 and TLR9 Regulate Interleukin 23 and 17 Production in a Murine Model of Gram Negative Bacterial Pneumonia

Toll like receptors play an important role in lung host defense against bacterial pathogens. In this study, we investigated independent and cooperative functions of TLR4 and TLR9 in microbial clearance and systemic dissemination during Gram-negative bacterial pneumonia. To access these responses, wildtype Balb/c mice, mice with defective TLR4 signaling (TLR4lps-d), mice deficient in TLR9 (TLR9−/−) and TLR4/9 double mutant mice (TLR4lps-d/TLR9−/−) were challenged with K. pneumoniae, then time-dependent lung bacterial clearance and systemic dissemination determined. We found impaired lung bacterial clearance in TLR4 and TLR9 single mutant mice, whereas the greatest impairment in clearance was observed in TLR4lps-d/TLR9−/− double mutant mice. Early lung expression of TNF-α, IL-12, and chemokines was TLR4 dependent, while IFN-γ production and the later expression of TNF-α and IL-12 was dependent on TLR9. Classical activation of lung macrophages and maximal induction of IL-23 and IL-17 required both TLR4 and TLR9. Finally, the i.t. instillation of IL-17 partially restored anti-bacterial immunity in TLR4lps-d/TLR9−/− double mutant mice. In conclusion, our studies indicate that TLR4 and TLR9 have both non-redundant and cooperative roles in lung innate responses during Gram-negative bacterial pneumonia and are both critical for IL-17 driven antibacterial host response

Why my photos look sideways or upside down? Detecting Canonical Orientation of Images using Convolutional Neural Networks

Image orientation detection requires high-level scene understanding. Humans use object recognition and contextual scene information to correctly orient images. In literature, the problem of image orientation detection is mostly confronted by using low-level vision features, while some approaches incorporate few easily detectable semantic cues to gain minor improvements. The vast amount of semantic content in images makes orientation detection challenging, and therefore there is a large semantic gap between existing methods and human behavior. Also, existing methods in literature report highly discrepant detection rates, which is mainly due to large differences in datasets and limited variety of test images used for evaluation. In this work, for the first time, we leverage the power of deep learning and adapt pre-trained convolutional neural networks using largest training dataset to-date for the image orientation detection task. An extensive evaluation of our model on different public datasets shows that it remarkably generalizes to correctly orient a large set of unconstrained images; it also significantly outperforms the state-of-the-art and achieves accuracy very close to that of humans

C‐C chemokine‐induced eosinophil chemotaxis during allergic airway inflammation

The production of eosinophil‐specific chemotactic factors during allergic airway responses may be a pivotal event resulting in eosinophil accumulation, activation, and airway damage. Recent studies have identified specific chemokines that may play crucial roles in recruitment of eosinophils to the site of allergic reactions. In this study we have utilized an established model of schistosome egg antigen (SEA)‐mediated allergic responses to examine the role of specific C‐C chemokines [macrophage inflammatory protein‐1α (MIP‐1α), RANTES, and monocyte chemoattractant protein‐1 (MCP‐1)] in eosinophil recruitment. We have previously identified a role for MIP‐1α in eosinophil accumulation in the lung and airway during allergic airway inflammation. We extend those studies using in vitro eosinophil chemotaxis to establish that both MIP‐1α and RANTES are potent eosinophil chemotactic factors in lungs during allergic airway responses. Morphometric analysis demonstrated a peribronchial accumulation of eosinophils within the lungs beginning at 8 h, peaking at 24 h, and plateauing at 48–96 h after allergen (SEA) challenge. Utilizing whole‐lung homogenates from allergen‐challenged mice, in vitro eosinophil chemotactic assays demonstrated significant increases in eosinophil chemotactic activity with 8‐h lung homogenates and peak activity with samples from 24‐h lung homogenates. These data correlated with the morphometric analysis of peribronchial eosinophil accumulation in situ. When lung homogenates from allergen‐challenged mice were preincubated in vitro with antibodies specific for MIP‐1α, RANTES, or MCP‐1, a significant reduction in eosinophil chemotaxis was observed with only MIP‐1α and RANTES neutralization. Altogether, these studies indicate that RANTES and MIP‐1α are major eosinophil chemotactic factors produced during allergic airway responses. J. Leukoc. Biol. 60:573–578; 1996.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141543/1/jlb0573.pd

Metabolomics as a Driver in Advancing Precision Medicine in Sepsis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138226/1/phar1974.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138226/2/phar1974_am.pd