Chapter-1 / Physiological Foundations - WHNLive Public Library

12111098V ~ .-"~"' .....b""", ".1TtrJrmol pH1I acidp?osphaloses (pota/oes)II P-fiucuronirint (oorine liver)1:AApll# 43., ~\,"r\'. -''',\~~1\ ,~215 24 6 8~6 2 4 6 8 7 2 4 6pt------8 8Fig. 117 Increasing activity of two Ivsosomalenzymes (examples) at T =37°Cin the transition from normal pH inhealthy tissue to the mean pH of tissuewith severe O 2 deficiency [141 )time span (autocytolysis time, e.g. 120 min).The cytolytic chain reaction is thus a slowprocess lasting many hours (e.g. 4-23 h, accordingto number of reaction steps and conditions).In connection with this we should thinkof the acute phase of the myocardiac infarction[200], which occurs in roughly'such time spans,for which we assume a lysosomal cytolyticchain reaction [2, 144, 171].The cell-damaging chain reaction can only reachgreat intensity in highly overacidified tissue,and even there remains in its "subcritical"range, i. e. it will only have effect-strengtheningproperties. That a cytolytic chain reaction mustoccur in highly overacidified tissue can be seenfrom the pH activation of the lysosomesalready described in [201], and just as clearlyfrom the typical courses of the pH/activitycurves of lysosomal hydrolases shown in Fig.117. The activity of such enzymes increasesnearly tenfold between the normal pH of thetissue and a pH level ~ 6.0. A severely damagingeffect on the adjacent cells must result inthe acidic milieu of such enzymes reaching theextracellular space.Added to this is the fact that the drainage ofthese enzymes is made much more difficult bythe inhibited microcirculation which prevailsin severely overacidified tissue. This must leadto an increased concentration of lysosomalenzymes in the intercapillary spa~e, and ~hus toa further strengthening of the cham reachon.The stop in O 2 supply when death occurs canbe regarded as a border case of ~2 defi~iency,both as regards its intensity and Its ~pat~al e.xtenion. As suggested in the presentatIOn m FIg.118, lysosomal cytolysis and cytolytic. chain. .living organism, in order to initiate its generaldisintegration immediately after death [202].The lysosomal cytolytic chain reaction has beenthe object of several investigations carried outsince 1965, which are summarized comprehensivelyin [2, 141, 171]. In a series of in vitroand in vivo experiments, experimental indicesfor the in vivo existence of the cytolytic chainreaction in highly overacidified tissue werefound:1. Damage of cancer cells by addition of cylysedcells [203];"2. Damage of cancer cells by isolated lysosomesor lysosomal enzymes [204];3. Release of lysosomal enzymes in and fromcancer cells at pH = 6.2 and 40°C hyperthermia[205, 206];4. pH-dependent strengthening of cell damagein the human skin [207];5. Considerable increase of cell damage by afactor of 20 in a cell uspension with increasingcell den ity; fa t ad orption ofextracellular indicator enzyme to urroundingcells [208].An expansion of lysosomal cytolysis to a cytolyticchain reaction must always be expectedin deficient O 2 supply in tissue, when th re is amarked drop in the tissue pH, i. e. accordin toFig. 109, when the tissue area affect d b 0deficiency has a volume of V 10-100 mmor more (exampl : myocardial infar tion inflammation).The chain rea tion pr d up tthe geometrical limit of th ov ra idifi ati nand th rca wh n it r ache uffi intiuppli d ti u parti ularl h n it r a hI r I v I