Eicosanoids and other oxylipins in liver injury, inflammation and liver cancer development.

Liver cancer is a malignancy developed from underlying liver disease that encompasses liver injury and metabolic disorders. The progression from these underlying liver disease to cancer is accompanied by chronic inflammatory conditions in which liver macrophages play important roles in orchestrating the inflammatory response. During this process, bioactive lipids produced by hepatocytes and macrophages mediate the inflammatory responses by acting as pro-inflammatory factors, as well as, playing roles in the resolution of inflammation conditions. Here, we review the literature discussing the roles of bioactive lipids in acute and chronic hepatic inflammation and progression to cancer.

Recombinant Aspergillus fumigatus antigens Asp f 3 and Asp f 9 in liposomal vaccine protect mice against invasive pulmonary aspergillosis.

Invasive pulmonary aspergillosis caused by the ubiquitous mold Aspergillus fumigatus is a major threat to immunocompromised patients, causing unacceptably high mortality despite standard of care treatment, and costing an estimated $1.2 billion annually. Treatment for this disease has been complicated by the emergence of azole resistant strains of A. fumigatus, rendering first-line antifungal therapy ineffective. The difficulties in treating infected patients using currently available drugs make immunotherapeutic vaccination an attractive option. Here, we demonstrate the efficacy of VesiVax® adjuvant liposomes, consisting of a combination of two individual liposome preparations, to which two recombinant A. fumigatus surface antigens, Asp f 3 and Asp f 9 (VesiVax® Af3/9), have been chemically conjugated. Using a murine model, we demonstrate that VesiVax® Af3/9 is protective against infection by azole resistant strains of A. fumigatus in both steroid-suppressed and neutropenic mice as quantified by improved survival and reduced fungal burden in the lungs. This protection correlates with upregulation of IL-4 produced by splenocytes, and the presence of Asp f 3 and Asp f 9 specific IgG2a antibodies in the serum of mice given VesiVax® Af3/9. Furthermore, mice given VesiVax® Af3/9 with a subsequent course of liposomal amphotericin B (AmBisome®) had improved survival over those given either treatment alone, indicating a benefit to VesiVax® Af3/9 vaccination even in the case of infections that require follow-up antifungal treatment. These data demonstrate that prophylactic vaccination with VesiVax® Af3/9 is a promising method of protection against invasive pulmonary aspergillosis even as the changing face of the disease renders current therapies ineffective.

Hepatic macrophage mediated immune response in liver steatosis driven carcinogenesis.

Obesity confers an independent risk for carcinogenesis. Classically viewed as a genetic disease, owing to the discovery of tumor suppressors and oncogenes, genetic events alone are not sufficient to explain the progression and development of cancers. Tumor development is often associated with metabolic and immunological changes. In particular, obesity is found to significantly increase the mortality rate of liver cancer. As its role is not defined, a fundamental question is whether and how metabolic changes drive the development of cancer. In this review, we will dissect the current literature demonstrating that liver lipid dysfunction is a critical component driving the progression of cancer. We will discuss the involvement of inflammation in lipid dysfunction driven liver cancer development with a focus on the involvement of liver macrophages. We will first discuss the association of steatosis with liver cancer. This will be followed with a literature summary demonstrating the importance of inflammation and particularly macrophages in the progression of liver steatosis and highlighting the evidence that macrophages and macrophage produced inflammatory mediators are critical for liver cancer development. We will then discuss the specific inflammatory mediators and their roles in steatosis driven liver cancer development. Finally, we will summarize the molecular pattern (PAMP and DAMP) as well as lipid particle signals that are involved in the activation, infiltration and reprogramming of liver macrophages. We will also discuss some of the therapies that may interfere with lipid metabolism and also affect liver cancer development.