The status of hemoglobin-based red cell substitutes.

Red cell substitutes are currently under development for use in a variety of surgery and trauma-related clinical conditions. The need for artificial oxygen-carrying fluids continues to be driven by the shortage of donor blood, the complex logistics of blood banking, the risk of virally transmitted diseases, current transfusion practices, and the projected increased demand for blood products in the future. The effort to develop a replacement for the red cell component has evolved over the last century and has presented a number of significant challenges including safety and efficacy concerns. Recent progress in understanding the fundamental interactions of hemoglobin with the body at the molecular, cellular and tissue levels has led to the production of improved red cell substitutes suitable for clinical testing. Currently, seven products are being tested for a variety of applications including trauma, surgery, sepsis, cancer and anemia. Although some of these trials were unsuccessful, the majority of the available products exert no toxicity or only low level side effects. Encouraging results in early clinical trials with oxygen-carrying fluids support further development of these products and have increased the hope that a usable oxygen-carrying fluid will soon be available in the clinic. The purpose of this review is to provide up-to-date information on the status of these products with special emphasis on pre-clinical and clinical experience.

ADAR1 is involved in the development of microvascular lung injury.

Deamination of adenosine on pre-mRNA to inosine is a recently discovered process of posttranscription modification of pre-mRNA, termed A-to-I RNA editing, which results in the production of proteins not inherent in the genome. The present study aimed to identify a role for A-to-I RNA editing in the development of microvascular lung injury. To that end, the pulmonary expression and activity of the RNA editase ADAR1 were evaluated in a mouse model of endotoxin (15 mg/kg IP)-induced microvascular lung injury (n=5) as well as in cultured alveolar macrophages stimulated with endotoxin, live bacteria, or interferon. ADAR1 expression and activity were identified in sham lungs that were upregulated in lungs from endotoxin-treated mice (at 2 hours). Expression was localized to polymorphonuclear and monocytic cells. These events preceded the development of pulmonary edema and leukocyte accumulation in lung tissue and followed the local production of interferon-gamma, a known inducer of ADAR1 in other cell systems. ADAR1 was found to be upregulated in alveolar macrophages (MH-S cells) stimulated with endotoxin (1 to 100 microg/mL), live Escherichia coli (5x10(7) colony-forming units), or interferon-gamma (1000 U/mL). Taken together, these data suggest that ADAR1 may play a role in the pathogenesis of microvascular lung injury possibly through induction by interferon.