The pathway by which intravenously injected ferritin molecules move from the blood plasma across the capillary wall has been investigated in the muscle of the rat diaphragm. At 2 min after administration, the ferritin molecules are evenly distributed in high concentration in the blood plasma of capillaries and occur within vesicles along the blood front of the endothelium. At the 10-min time point, a small number of molecules appear in the adventitia, and by 60 min they are relatively numerous in the adventitia and in phagocytic vesicles and vacuoles of adventitial macrophages. Thereafter, the amount of ferritin in the adventitia and pericapillary regions gradually increases so that at 1 day the concentration in the extracellular spaces approaches that in the blood plasma. Macrophages and, to a lesser extent, fibroblasts contain large amounts of ferritin. 4 days after administration, ferritin appears to be cleared from the blood and from the capillary walls, but it still persists in the adventitial macrophages and fibroblasts. At all time points examined, ferritin molecules within the endothelial tunic were restricted to vesicles or to occasional multivesicular or dense bodies; they were not found in intercellular junctions or within the cytoplasmic matrix. Ferritin molecules did not accumulate within or against the basement membranes. Over the time period studied, the concentration of ferritin in the blood decreased, first rapidly, then slowly, in two apparently exponential phases. Liver and spleen removed large amounts of ferritin from the blood. Diaphragms fixed at time points from 10 min to 1 day, stained for iron by the Prussian Blue method, and prepared as cleared whole mounts, showed a progressive and even accumulation of ferritin in adventitial macrophages along the entire capillary network. These findings indicate: (1) that endothelial cell vesicles are the structural equivalent of the large pore system postulated in the pore theory of capillary permeability; (2) that the basement membrane is not a structural restraint in the movement of ferritin molecules across the capillary wall; (3) that transport of ferritin occurs uniformly along the entire length of the capillary; and (4) that the adventitial macrophages monitor the capillary filtrate and partially clear it of the tracer.

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