Small bowel obstruction from luminal gastrointestinal metastasis is a rare, but recognized, presentation of metastatic breast cancer. Herein, we report a case of a small bowel obstruction from lobular breast cancer metastasis to the terminal ileum, occurring over a decade after diagnosis and treatment of the initial primary cancer. Our review highlights the presentation and management of this unusual disease manifestation, including diagnosis of the gastrointestinal process, identification of the primary cancer, surgical treatment of the abdominal pathology, systemic therapy for metastatic disease, and survival data for patients with this disease process.
Caveolin-1 (Cav1), the scaffolding protein of caveolae, has been shown to play an important role in host defense and inflammation. However, the underlying molecular basis for these actions remains elusive. Here, using double mutant mice with genetic deletions of Cav1 and NOS3, we show that chronic endothelial nitric oxide synthase (eNOS) activation secondary to loss of Cav1 serves a crucial immunomodulatory function through tyrosine nitration-mediated impairment of interleukin-1 receptor associated kinase (IRAK)4, a signaling component required for nuclear factor-kappaB activation and innate immunity. We observed an eNOS-dependent decrease in the plasma concentration of pro-inflammatory cytokines and marked improvement of survival in Cav1(-/-) mice following lipopolysaccharide challenge. Activation of eNOS secondary to loss of Cav1 resulted in decreased activation of nuclear factor-kappaB in response to lipopolysaccharide challenge, and thereby protected the animals from lipopolysaccharide-induced lung injury. IRAK4 was prominently nitrated in Cav1-deficient endothelial cells, whereas eNOS deletion in Cav1-deficient endothelial cells resulted in marked decrease of IRAK4 nitration and restored the inflammatory response after lipopolysaccharide challenge. Furthermore, in vitro nitration of IRAK4 resulted in impairment of the kinase activity. Thus, eNOS activation secondary to loss of Cav1 signals dampening of the innate immune response to lipopolysaccharide through IRAK4 nitration and the resultant impairment of kinase activity, and consequently mitigates inflammatory lung injury.
The goal of this study was to determine the role of integrin-mediated adhesion of bone-marrow-derived progenitor cells (BMPCs) as a requirement for the endothelial barrier protection in a lung injury model. C57BL mice were used as the source for BMPCs, which were characterized as CD34(+) and fetal liver kinase-1 (Flk1)(+) and also an expression of a repertoire of integrins. We used a mouse model of bacterial lipopolysaccharide (LPS)-induced lung vascular injury and edema formation to test the effects of BMPC integrin expression in preventing endothelial barrier injury. Adhesion of BMPCs to purified extracellular matrix proteins induced focal adhesion kinase (Fak) phosphorylation and formation of branching point structures in a alpha(4) and alpha(5) integrin-dependent manner. BMPCs expressing red fluorescent protein (RFP) were administered via the retro-orbital venous route in mice treated intraperitonially with LPS (7.5 mg/kg body weight). We observed increased retention of RFP-labeled Flk1(+) and CD34(+) BMPCs for up to 8 weeks in mice injured with LPS. BMPC transplantation increased survival by 50% (at 72-96 hours after LPS) and reduced lung vascular injury and extravascular water content induced by LPS. However, blocking with anti-alpha(4) or anti-alpha(5) integrin antibody or shRNA-mediated silencing of alpha(4) or alpha(5) integrins in donor BMPCs failed to prevent the vascular injury or edema formation and mortality. Thus, alpha(4) and alpha(5) integrin-dependent adhesion of BMPCs in lung tissue plays a critical role in preventing lung vascular injury and increasing survival in a mouse model of LPS-induced acute lung injury.
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