Sepsis, the systemic inflammatory response to microbial infection, induces changes in both innate and adaptive immunity that presumably lead to increased susceptibility to secondary infections, multi-organ failure and death. Using a model of murine polymicrobial sepsis whose severity approximates human sepsis, we examined outcomes and defined requirements for survival after secondary Pseudomonas aeruginosa pneumonia or disseminated Listeria monocytogenes infection. We demonstrate that early after sepsis, neutrophil numbers and function are decreased, whereas monocyte recruitment through the CCR2/MCP1 pathway and function are enhanced. Consequently, lethality to Pseudomonas pneumonia is increased early but not late after induction of sepsis. In contrast, lethality to listeriosis, whose eradication is dependent upon monocyte/macrophage phagocytosis, is actually decreased both early and late after sepsis. Adaptive immunity plays little role in these secondary infectious responses. This study demonstrates that sepsis promotes selective early, impaired innate immune responses, primarily in neutrophils, that lead to a pathogen-specific, increased susceptibility to secondary infections.

Neutrophils are essential for successful host eradication of bacterial pathogens and for survival to polymicrobial sepsis. During inflammation, the bone marrow provides a large reserve of neutrophils that are released into the peripheral circulation where they traverse to sites of infection. Although neutrophils are essential for survival, few studies have investigated the mechanisms responsible for neutrophil mobilization from the bone marrow during polymicrobial sepsis. Using a cecal ligation and puncture model of polymicrobial sepsis, we demonstrate that neutrophil mobilization from the bone marrow is not dependent on TLR4, MyD88, TRIF, IFNARα/β or CXCR2 pathway signaling during sepsis. In contrast, we observe that bone marrow CXCL12 mRNA abundance and specific CXCL12 levels are sharply reduced, while splenic CXCR4 mRNA and cell surface expression are increased during sepsis. Blocking CXCL12 activity significantly reduced the blood neutrophilia by inhibiting bone marrow release of granulocytes during sepsis. CXCL12 inhibition, however, had no impact on the expansion of bone marrow neutrophil precursors and hematopoietic progenitors. Bone marrow neutrophil retention by CXCL12 blockade prevented blood neutrophilia, inhibited peritoneal neutrophil accumulation, allowed significant peritoneal bacterial invasion and elevated polymicrobial sepsis mortality. We conclude that changes in the pattern of CXCL12 signaling during sepsis are essential for neutrophil bone marrow mobilization and host survival while having little impact on bone marrow granulopoiesis.

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Background: Endometrial clear-cell carcinoma (ECCC) is a rare and particularly aggressive form of endometrial cancer that accounts for only 1%-6% of all cases. ECCC is more commonly found in older African American women. This report highlights the importance of tissue sampling in the atypical patient. Case: A 31-year-old Caucasian female presented with heavy menses and had an abnormal Papanicolaou smear. Cervical cytology and histology specimens were obtained. Results: A timely evaluation was performed. Endometrial sampling was found to be remarkable for ECCC. She had exploratory laparotomy, total abdominal hysterectomy and bilateral salpingooophorectomy, and pelvic and para-aortic lymph-node dissection Final staging was reported as Stage 1A grade 3 ECCC. She received 6 cycles of carboplatin/taxol. A follow-up computed tomography scan 6 months later of her chest, abdomen, and pelvis showed no evidence of residual or recurrent disease. Conclusions: ECCC is a rare, aggressive endometrial cancer. There are no existing screening tools for ECCC. Disease presentation is not always typical. Thorough evaluation of patients with menstrual irregularities associated with abnormal Papanicolaou smears may prevent delayed diagnosis of malignancy in the atypical patient. ( J GYNECOL SURG XX:1)