Swelling of hepatocytes injured by oxidative stress suggests pathological changes related to macromolecular crowding

A fundamental property of living matter is the ability to establish and maintain order. Mild changes in cell volume have a role in metabolic control. Furthermore, cellular swelling is a way of living cells to react to a variety of stressors. Data from experimental pathology, biochemistry and biophysics and theoretical arguments from biology, biochemical evolution, cytology and biophysics are considered to attempt an integration of several current concepts on different subjects (intracellular compartmentation, cellular swelling, macromolecular crowding, perturbing and non-perturbing solutes). The purpose is to provide a framework for conceptualizing in modern terms the question whether cellular swelling induced by oxidative stress should be considered merely a cell adaptation balanced by antioxidant defenses and by other biochemical devices apt to preserve the intracellular environment and normal cell functioning, or whether swelling of high amplitude should be regarded as a true pathological change. The basic question dated 1982: "how crowded is the cytoplasm?" is a matter for discussion as far as swollen cells are concerned. This paper examines the liver for cellular swelling of high amplitude (about+30%) caused by iron or by thyroid hormone+iron (histological picture of "cloudy swelling") or the steatogenic poison CCl(4), also known as a source of oxyradicals, which causes an even more pronounced cellular swelling. In CCl(4)-toxic fatty liver the strong increase of tissue water is substantially masked by the parallel increase of tissue dry solids due to fat accumulation. This example of a "tissue dilution artefact" is discussed in connection with the increase of tissue water also in toxic fatty liver induced by white phosphorus and ethanol. In CCl(4)-toxic fatty liver the normal K(+)/Na(+) ratio (about 3) is substantially maintained, whereas the concentrations of the two cations ("perturbing osmolytes") in tissue water are noticeably decreased, a finding which was not further studied at the time the observations were made because biochemistry was not yet advanced enough to allow an explanation. Today, a logic hypothesis is that an increase of non-perturbing solutes such as taurine and betaine, maintains the physiological intracellular osmotic pressure and that the harmful effects of CCl(4) are limited because of the protective effects of these molecules and of molecular chaperones against damage by oxyradicals. However, as a consequence of cellular swelling, intracellular changes in ionic strength and macromolecular crowding should occur thus affecting enzyme activities. Models and techniques apt to investigate this problem experimentally are suggested.