Septic Shock - Nitric Oxide in Disease

SEPTIC SHOCK

Sepsis is a systemic inflammatory response caused by infection. Endotoxin components from the bacterial wall along with endogenously generated tumor necrosis factor-α and other cytokines induce synthesis of iNOS in macrophages, neutro-phils, and T cells, as well as hepatocytes, smooth muscle cells, endothelial cells, and fibroblasts. This widespread generation of NO results in exaggerated hypotension, shock, and, in some cases, death. This hypotension is reduced or reversed by NOS inhibitors in humans as well as in animal models (Table 19–3). A similar reversal of hypotension is produced by compounds that prevent the action of NO, such as the sGC inhibitor meth-ylene blue. Furthermore, knockout mice lacking a functional iNOS gene are more resistant to endotoxin than wild-type mice. However, despite the ability of NOS inhibitors to ameliorate hypotension in sepsis, there is no overall improvement in sur-vival in patients with gram-negative sepsis treated with NOS inhibitors. The absence of benefit may reflect the inability of the NOS inhibitors used in these trials to differentiate between NOS isoforms, or may reflect concurrent inhibition of beneficial aspects of iNOS signaling.