Future perspectives on regulating pro-and anti-inflammatory responses in sepsis.

Therapy for severe sepsis and septic shock remains a major unmet medical need and novel treatments to regulate the disordered inflammatory response in sepsis are needed if improved outcomes in sepsis are to be realized in the future. Current therapy is primarily supportive and includes timely administration of antibiotics, source control of infection, aggressive fluid resuscitation, organ support and use of activated protein C where clinically indicated. Bacterial mediators including endotoxin and superantigens as well endogenous proinflammatory cytokines are critical to the pathogenesis of sepsis-induced organ failure and are being targeted with numerous molecules and removal devices. Additional therapeutic strategies are focused at restoring the natural anticoagulant levels, blocking deleterious effects of the complement cascade, preserving mitochondrial function, and inhibiting excessive lymphocyte apoptosis. Molecules with pluripotent activity such as inter-alpha inhibitor proteins, sirtuin activators and estrogen-receptor ligands are also being investigated. Efforts are underway to re-establish microbial clearance mechanisms and permit immune reconstitution following sepsis-induced immune suppression. A review of the most current agents being investigated and their current status are presented in this chapter. The organization of this chapter includes sections addressing therapies targeting microbial mediators, including endotoxin, as well as therapies targeting inflammation and coagulation. There is also a section on agents targeting novel mediators and pathways.

Inter-α inhibitor proteins: a novel therapeutic strategy for experimental anthrax infection.

Human inter-α inhibitor proteins are endogenous human plasma proteins that function as serine protease inhibitors. Inter-α inhibitor proteins can block the systemic release of proteases in sepsis and block furin-mediated assembly of protective antigen, an essential stop in the intracellular delivery of the anthrax exotoxins, lethal toxin and edema toxin. Inter-α inhibitor proteins administered on hour or up to 24 h after spore challenge with Bacillus anthracis Sterne strain protected mice from lethality if administered with antimicrobial therapy (P < 0.001). These human plasma proteins possess combined actions against anthrax as general inhibitors of excess serine proteases in sepsis and specific inhibitors of anthrax toxin assembly. Inter-α inhibitor proteins could represent a novel adjuvant therapy for the treatment of established anthrax infection.