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

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 CCl4, also known as a source of oxyradicals, which causes an even more pronounced cellular swelling. In CCl4-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 CCl4-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 CCl4 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.