DNA damage and p21(WAF1/CIP1/SDI1) in experimental injury of the rat adrenal cortex and trauma-associated damage of the human adrenal cortex

In vivo models are needed to study the reactions of tissues to DNA damage, such as the induction of the cyclin-dependent kinase inhibitor p21, indicat ing potential repair of the damage, versus apoptosis, indicating the elimin ation of the damaged cells. Damage to DNA occurs in tissues during shock, s epsis, and other critical medical conditions. Previous studies have found e vidence of damage to the cortex of adrenal glands from organ donors who had undergone severe trauma prior to death. The present experiment studied rat s under experimental interventions of clinical relevance to patients with c onditions that put them at risk for damage to the adrenal glands. These int erventions comprised ischaemia and reperfusion injury, sepsis following cae cal ligation and puncture, acute pancreatitis, and administration of chemic al agents (zymosan and acrylonitrile). All the interventions caused an incr ease in p21 mRNA as assessed by northern blotting and in situ hybridization . Increased nuclear p21 protein was shown by immunohistochemistry. All the interventions caused damage to DNA, as shown by labelling of available 3' t ermini of single-strand breaks with terminal transferase. The number of cel ls undergoing apoptosis, visualized by ligation of a hairpin oligonucleotid e probe to double-strand breaks in DNA, was much lower. In rat adrenal glan ds, apoptotic cells were infrequent under all the conditions studied. They were more abundant in human organ donor adrenal glands that were previously shown to have extensive DNA damage accompanied by induction of p21. The si milarity of the effects of a wide variety of surgical interventions and che mical agents suggest a common pathophysiological mechanism which is not spe cific to the initiating injury. Experimental injury of the rat adrenal cort ex provides a model for investigating the role of organ DNA damage and of m ediators of the response to DNA damage, such as p21. Copyright (C) 1999 Joh n Wiley & Sons, Ltd.