Reactive oxygen species produced at toxic levels are damaging species. When produced at sub-toxic levels, however, they are involved as second messengers in numerous signal transduction pathways. In addition to these findings, we can add the concept that iron (often viewed as the ‘villain’ in free radical biology) can also be considered as a signalling species. Iron is intimately involved in the regulation of its own storage, compartmentalization and turnover. During adult respiratory distress syndrome (ARDS) and sepsis, such regulation may be aberrant or altered in some predisposed way. Such changes may have profound implications for tissue damage, and for the modulation of the inflammatory response in these patients. The search for a genetic predisposition in patients that leads to the development of ARDS associated with abnormalities in iron turnover and signalling would seem to be an important and logical progression for studies into the disease. These may lead eventually to the design of effective treatment regimens that involve the control of iron.

1. The extracellular proteins caeruloplasmin and transferrin have important antioxidant properties by virtue of the fact that they inhibit iron-dependent free radical production, and ensuing damage to cells. 2. Albumin is a plasma protein which can loosely bind iron, but the redox activity of this iron has not been fully investigated. 3. The ability of albumin to bind iron and to prevent iron-dependent lipid peroxidation in vitro was investigated using liposomes and a rat brain homogenate system. 4. The iron-binding capacity of albumin was found to be substantial, and albumin inhibited lipid peroxidation in a concentration-dependent manner in both systems used. 5. This antioxidant property of albumin may be especially important in the plasma of babies born prematurely, in whom transferrin and caeruloplasmin concentrations are often very low, and in whom non-transferrin-bound iron has been detected in the plasma.

1. The accumulation in the lung of the plasma protein transferrin was determined in 44 patients with widespread pulmonary infiltrates of various causes and in 11 healthy volunteers using a double-isotope method based on labelling in vivo of circulating transferrin with indium and erythrocytes with technetium. 2. In 22 patients meeting criteria for the adult respiratory distress syndrome (ARDS) the mean transferrin accumulation rate was threefold greater ( P < 0.005) than in 22 patients not meeting these criteria, although most possessed an appropriate risk factor for ARDS, in addition to extensive radiographic changes. 3. The double-isotope method did not completely separate patients with ARDS from those not meeting the criteria or from control subjects and cannot be considered a diagnostic test for the condition. Statistically significant rates of transferrin accumulation, however, occurred more frequently in patients with ARDS (82%) than in controls (64%) or in those without ARDS (59%).

1. The binding of transferrin and the uptake of iron by rat bone-marrow-cell suspensions was investigated by the use of transferrin doubly labelled with 125 I and 59 Fe. 2. The pattern of transferrin binding was found to depend on the transferrin concentration in the incubation medium. At relatively low concentrations, binding of transferrin at 0–4 °C was lower than the binding at 37°C. At higher concentrations no difference could be observed between binding at 0–4°C and at 37°C. This phenomenon was explained in terms of a rapid non-specific adsorption of transferrin at 0–4°C, which takes place especially at higher transferrin concentrations, and a specific binding of transferrin at 37°C observed presumably at low concentrations. 3. The maximum number of specific transferrin-binding sites was found to be approximately 190 000 sites per rat reticulocyte and 330 000 sites per nucleated rat bone-marrow cell. The latter number corresponds to 500 000–700 000 sites per nucleated erythroid cell. 4. It was concluded that maturation of the erythroid cell is accompanied with a progressive loss of transferrin binding sites on the cell membrane. 5. When bone-marrow cells obtained after incubation with doubly-labelled transferrin were lysed with distilled water or with the detergent Nonidet P-40, differences in the subcellular distribution of the radioactivities could be observed. 6. It was concluded that the membrane fraction contains appreciable amounts of 59 Fe not bound to 125 I-labelled transferrin, which indicates that dissociation of the iron—transferrin complex is one of the earlier steps in the mechanism of iron uptake by erythroid cells.

1. Transferrin was isolated from umbilical cord blood by means of gel filtration on Sephadex G-150 and ion-exchange chromatography on DEAE-Sephadex A-50, and its properties were compared with those of transferrin isolated from human adult blood. 2. Both glycoproteins were able to bind a maximum of two atoms of iron per molecule and have very similar amino acid and carbohydrate compositions. 3. The molecular weight of cord-blood transferrin, assessed by equilibrium centrifugation, was 78 200, and its sedimentation velocity appeared to be 5.2S. 4. Cord-blood transferrin and adult blood transferrin were found to be immunochemically identical. 5. No differences could be detected between the transferrins in their capacities to deliver iron to immature erythrocytes derived from rat bone marrow, which indicates that the rapid transport of iron across the placenta cannot be explained by differences between foetal and maternal transferrin.

1. The inhibitory (antioxidant) effect of serum on the autoxidation of tissue polyunsaturated fatty acids has been investigated. 2. Dialysis studies, DEAE-cellulose chromatography, gel filtration, immunoelectrophoresis and immunodiffusion experiments showed that this effect is the function of two serum protein fractions. 3. One fraction was identified as transferrin. The second fraction includes caeruloplasmin. 4. Studies with radioactively labelled α-tocopherol showed that serum tocopherol in the physiological concentration range contributes only marginally to the total antioxidant activity of serum. 5. These findings are discussed in the wider context of biological antioxidant protection.

1. Experiments are reported which aimed at determining whether transferrin loses sialyl residues from the carbohydrate side-chains during the biological lifetime of the molecule. To explore this possibility, transferrin fractions of relatively high sialic acid content (referred to as sialotransferrin) were prepared from purified rabbit and bovine transferrin by preparative polyacrylamide-gel electrophoresis. After labelling with 125 I, the preparations were injected into a group of three rabbits each. From the plasma samples obtained between 1 h and 6–8 days after injection, transferrin was partially purified, mixed with 131 I-labelled asialotransferrin of the corresponding species and run in preparative polyacrylamide-gel electrophoresis. In each specimen examined, the 125 I radioactivity migrated ahead of the marker asialotransferrin, and no portion of the dose was detected with the electrophoretic mobility of asialotransferrin. 2. Evidence is presented that bovine transferrin desialylated in vitro remains detectable in the plasma of rabbits for intervals which are comparable with those found in previous studies with rabbit asialotransferrin. 3. A mathematical model is described for the computation of asialo- to sialotransferrin radioactivity ratios in the plasma, continuous desialylation of pulse-injected sialotransferrin being assumed. Calculations were made at various hypothetical rates of desialylation. 4. On the basis of the experimental data and the model it is concluded that transferrin (both rabbit and bovine) is not subjected to systematic desialylation in rabbits. Random desialylation of some transferrin could take place at rates less than 5% of the fractional catabolic rate of transferrin, which would be without any biological significance.

1. A radial immunodiffusion technique was used to determine the concentrations of five rat serum proteins, slow α 1 - and α 2 -globulin, transferrin, albumin and γ 2 -globulin before and after the induction of immune complex nephritis. 2. Four weeks after immunization with renal tubular antigen significant increases in transferrin, slow α 2 -globulin and γ 2 -globulin concentrations were observed but albumin showed a significant fall and slow α 1 -globulin did not change. 3. After the development of proteinuria 7 weeks after immunization significant falls in the concentrations of albumin transferrin and γ 2 -globulin were noted along with significant increases in the macroglobulins, slow α 1 - and α 2 -globulin, the changes being similar to those seen in the nephrotic syndrome in man. 4. At the end of the experiment the typical ultrastructural features of immune complex nephritis were observed.