BackgroundInflammation in the early stages of sepsis is governed by the innate immune response. Costimulatory molecules are a receptor/ligand class of molecules capable of regulation of inflammation in innate immunity via macrophage/neutrophil contact. We recently described that CD80/86 ligation is required for maximal macrophage activation and CD80/86−/− mice display reduced mortality and inflammatory cytokine production after cecal ligation and puncture (CLP). However, these data also demonstrate differential regulation of CD80 and CD86 expression in sepsis, suggesting a divergent role for these receptors. Therefore, the goal of this study was to determine the individual contribution of CD80/86 family members in regulating inflammation in sepsis.Methodology/Principal FindingsCD80−/− mice had improved survival after CLP when compared to WT or CD86−/− mice. This was associated with preferential attenuation of inflammatory cytokine production in CD80−/− mice. Results were confirmed with pharmacologic blockade, with anti-CD80 mAb rescuing mice when administered before or after CLP. In vitro, activation of macrophages with neutrophil lipid rafts caused selective disassociation of IRAK-M, a negative regulator of NF-κB signaling from CD80; providing a mechanism for preferential regulation of cytokine production by CD80. Finally, in humans, upregulation of CD80 and loss of constitutive CD86 expression on monocytes was associated with higher severity of illness and inflammation confirming the findings in our mouse model.ConclusionsIn conclusion, our data describe a differential role for CD80 and CD86 in regulation of inflammation in the innate immune response to sepsis. Future therapeutic strategies for blockade of the CD80/86 system in sepsis should focus on direct inhibition of CD80.
The initial phase of sepsis is characterized by massive inflammatory cytokine production which contributes to multisystem organ failure and death. Costimulatory molecules are a class of receptors capable of regulating cytokine production in adaptive immunity and recent studies describe their presence on neutrophils and monocytes, suggesting a potential role for regulating cytokine production in innate immunity. The purpose of this study is to determine the role for OX40-OX40L interaction in the innate immune response to polymicrobial sepsis. Humans with sepsis demonstrated upregulation of OX40L on both monocytes and neutrophils, with mortality and ICU stay correlating with expression levels. In an animal model of polymicrobial sepsis, a direct role for OX40L in regulating inflammation was evidenced by improved survival, decreased cytokine production and a decrease in remote organ damage in OX40L −/− mice. The finding of similar results with an OX40L antibody suggests a potential future therapeutic role for OX40L blockade in sepsis. The inability of α-OX40L to provide significant protection in macrophagedepleted mice establishes macrophages as an indispensible cell type within the OX40/OX40L axis that helps to mediate the clinical signs of disease in sepsis. Conversely, the protective effect of α-OX40L antibody in RAG1 −/− mice, further confirms a T-cell independent role for OX40L stimulation in sepsis. In conclusion, our data provide a novel in vivo role for OX40-OX40L system in the innate immune response during polymicrobial sepsis and suggests a potential beneficial role for therapeutic blockade of OX40L in this devastating disorder.
Bronchial schwannomas are rare tumors that arise from Schwann cells and account for a very small percentage of primary lung tumors. This case report describes a rare incidental finding of a bronchial schwannoma discovered in the left lower lobe secondary carina via bronchoscopy in a 71-year-old female who presented with minimal symptoms.
Necrotizing pneumonia is a rare but potentially life-threatening complication of pulmonary blastomycosis, a fungal infection caused by inhaling spores of the fungus Blastomyces dermatitidis. This case report describes a 56-year-old male who presented with worsening malaise, subjective fevers and chills, night sweats, and a productive cough. Further evaluation revealed a right upper lobe necrotizing pneumonia secondary to pulmonary blastomycosis.
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