Inflammatory response apoptosis

The mechanisms of secondary injury include neurotransmitter-mediated excitotoxicity free-radical injury to cell membranes, electrolyte imbalances, mitochondrial dysfunction, inflammatory responses, apoptosis, secondary ischemia from vasospasm, focal microvascular occlusion, and vascular injury (Werner and Engelhard, 2007). These events can lead to cerebral edema and further increases in ICR The detailed molecular mechanisms of these events are described later in this chapter. 

In the very early phases of the acute inflammatory response most of the cells invading the damaged area are polymorphonuclear neutrophils, also denoted as PMNs, which serve as initial line of defense and source of proinflammatory cytokines. These cells, which usually live for 4-5 days, circulate in the blood until they are attracted by chemokines into injured tissues. Whereas physical injury does not recruit many neutrophils, infections with bacteria or fungi elicit a striking neutrophil response. The characteristic pus of a bacterial abscess is composed mainly of apoptotic (apoptosis) and necrotic PMNs. Emigration of neutrophils from the blood starts with a process denoted as margination where neutrophils come to lie at the periphery of flowing blood cells and adhere to endothelial cells (Fig. 1). L-Selectin is expressed... 

Both PAF [57] and COX-2 are potent mediators of the injury/inflammatory response (Fig. 33-5). PAF and COX-2 are also interrelated in neuronal plasticity. The PAF transcriptional activation of COX-2 may provide clues about novel neuronal cell-death pathways. In fact, the delayed induction of COX-2 by kainic acid precedes selective neuronal apoptosis by this agonist in the hippocampus [42,58]. 

Host cells are killed by cytotoxic T-ceUs or natural kiUer cells by the processes of necrosis or apoptosis. Necrosis leads to release of cell contents that can sufficiently disturb the tissue to initiate a local inflammatory response. However, the cell killed by apoptosis is then phagocytosed, which does not cause local disturbance, so that inflammation does not occur (Chapter 20). Apoptosis is achieved by two mechanisms release of toxic granules by the cytotoxic cells or by the binding of the cytotoxic ceU to the host ceU, via its death receptor protein (see below). 

Cell necrosis (not shown) should be distinguished from apoptosis. In cell necrosis, cell death is usually due to physical or chemical damage. Necrosis leads to swelling and bursting of the damaged cells and often triggers an inflammatory response. 

By contrast, cells undergoing apoptosis do not lyse, so there is no associated inflammatory response. 

Trigger programmed cell death (apoptosis) as opposed to random cell death (necrosis). This allows sub-lethal doses of photosensitiser, preventing damage and inflammatory response in healthy tissue. 

If the ATP depletion is too great, then apoptosis cannot proceed. Kupffer cell activation involving IFNy (interferon) and TNF-a is part of an inflammatory response in which nitric oxide and various cytokines are produced. 

Reactive oxygen species such as the hydroxyl radical, superoxide anion, and peroxynitrite are involved in many cellular processes including the inflammatory response. The best known antiinflammatory compound is ebselen (59, R = Ph). It is shown to be a neuroprotective agent and an inhibitor of free radical-induced apoptosis [20, 248, 249], It has undergone phase III clinical trials and is soon to become the first synthetic organoselenium therapeutic released on the market. 

---