Fig. 2.4 Morphologicchangesinreversibleandirreversiblecellinjury(necrosis).(A)Normalkidneytubuleswithviableepithelialcells.(B)Early(reversible)ischemicinjuryshowingsurfaceblebs,increasedeosinophiliaofcytoplasm,andswellingofoccasionalcells.(C)Necrotic(irreversible)injuryofepithelialcells,withlossofnucleiandfragmentationofcellsandleakageofcontents.(Courtesy of Drs. Neal Pinckard and M.A.Venkatachalam, University of Texas Health Sciences
Center, San Antonio,Texas.) barbiturates leads to a state of tolerance, marked by the need to use increasing doses of the drug to achieve the same effect. This adaptation stems from hypertrophy (an increase in volume) of the smooth ER of hepatocytes and a consequent increase in P-450 enzymatic activity. P-450– mediated modification of compounds sometimes leads to their detoxification, but in other instances converts them into a dangerous toxin; one such example involves carbon tetrachloride (CCl4), discussed later. Cells adapted to one drug demonstrate an increased capacity to metabolize other compounds handled by the same system. Thus, if patients taking phenobarbital for epilepsy increase their alcohol intake, they may experience a drop in blood concentration of the anti-seizure medication to subtherapeutic levels because of smooth ER hypertrophy in response to the alcohol.
With persistent or excessive noxious exposures, injured cells pass a nebulous “point of no return” and undergo cell death. The clinical relevance of defining this transition point is obvious—if the biochemical and molecular changes that predict cell death can be identified, it may be possible to devise strategies for preventing the transition from reversible to irreversible cell injury. Although there are no definitive morphologic or biochemical correlates of irreversibility, it is consistently characterized by three phenomena: the inability to restore mitochondrial function (oxidative phosphorylation and adenosine triphosphate [ATP] generation) even after resolution of the original injury; the loss of structure and functions of the plasma membrane and intracellular membranes; and the loss of DNA and chromatin structural integrity. As discussed in more detail later, injury to lysosomal membranes results in the enzymatic dissolution of the injured cell, which is the culmination of necrosis.
When cells are injured they die by different mechanisms, depending on the nature and severity of the insult.
• Severe disturbances, such as loss of oxygen and nutrient supply and the actions of toxins, cause a rapid and uncontrollable form of death that has been called “accidental” cell death. The morphological manifestation of accidental cell death is necrosis (Greek, necros = death) (
Table 2.1 ). Necrosis is the major pathway of cell death in many commonly encountered injuries, such as those resulting from ischemia, exposure to toxins, various infections, and trauma. Necrosis is traditionally considered the inevitable end result of severe damage that is beyond salvage and is not thought to be regulated by specific signals or biochemical mechanisms; in other words, necrosis happens accidentally because the injury is too severe to be repaired and many cellular constituents simply fail or fall apart.
• In contrast, when the injury is less severe, or cells need to be eliminated during normal processes, they activate a precise set of molecular pathways that culminate in death. Because this kind of cell death can be manipulated
Table 2.1 Features of Necrosis and Apoptosis http://ebooksmedicine.net