Heparin induced alterations in clearance and distribution of blood-borne microparticles following operative trauma.

The influence of systemic heparin administration on the vascular clearance and tissue distribution of blood-borne microparticles was evaluated in normal rats and rats after operation (laparotomy plus intestinal manipulation) utilizing an (131)I- colloid which is phagocytized by the reticuloendothelial system (RES). Intravenous heparin administration (100 USP/100g body weight) into normal animals three minutes prior to colloid injection (50 mg/lOOg) induced a significant increase in pulmonary localization of the microparticles as compared to nonheparinized control rats, while hepatic and splenic uptake were decreased. Surgical trauma decreased hepatic RE uptake and increased pulmonary localization of the microparticles when injected systemically at 60 minutes postsurgery. Heparin administration 60 minutes after surgery and three minutes prior to colloid injection, magnified the increased pulmonary localization response with an associated further depression of the RES. The ability of heparin to alter both RE clearance function and lung localization of microparticles was dose dependent and a function of the interval between heparin administration and systemic particulate infusion. Thus, low dose heparin administration was capable of stimulating RE activity while heparin in doses of excess of 50 USP units/lOOg body weight decreased RE function. These findings suggest that the functional state of the hepatic RE system can be greatly affected in a dose-dependent manner by systemic heparin administration which may influence distribution of blood-borne microparticles.

Decreased resistance to intravenous tumour-cell challenge during reticuloendothelial depression following surgery.

The influence of surgical stress on resistance to i.v. challenge with Walker 256 tumour cells was investigated in rats, with respect to the functional state of the reticuloendothelial system (RES). Phagocytic activity of the RES was evaluated by colloid (gelatinized [131I] "RE test lipid emulsion") clearance, and opsonin levels were determined by bioassay. Reticuloendothelial clearance capacity was significantly (P less than 0-05) depressed 60 min following surgery (coeliotomy plus jejunal enterotomy) as quantified by both humoral and cellular parameters of RE function. Phagocytic depression was primarily due to impaired hepatic Kupffer cell function and related to a deficiency in the phagocytic supporting capacity of plasma, also referred to as opsonic or recognition factor (RF) capacity. During the postoperative period of RES colloid clearance depression, pulmonary localization of the blood-borne test particulate matter increased. Rats challenged with 51Cr-labelled viable tumour cells at a dose of 1-0 X 106 i.v., either prior to or during the postoperative period of RE depression, manifested a significant (P less than 0-05) increment in pulmonary localization of the viable tumour cells, and a decrease (P less than 0-05) in hepatic clearance. Evaluation of survival patterns demonstrated a significant (P less than 0-01) decrease in host resistance to i.v. tumour cell challenge (2 X 103 cells) during the postoperative period of RE depression and hypo-opsonaemia. Sham-anaesthetized control animals survived 17-9 +/- 0-8 days, while animals challenged during the period of RE depression survived 7-9 +/- 0-4 days. An increased incidence of respiratory distress and nasal discharge was observed in the animals with impaired survival. Thus, surgical manipulation may transiently compromise RES systemic host defence and may be reflected in an increment in the pulmonary localization of blood-borne tumour cells. The relationship of this altered pattern of tumour cell distribution to the impaired survival remains to be determined, and warrants investigations.

Humoral mediated macrophage response during tumour growth.

Reticuloendothelial (RE) phagocytic and circulating plasma opsonic activity was evaluated in rats transplanted with the Walker 256 carcinoma tumour in an attempt to evaluate the role of opsonic protein in governing the functional state of the macrophage system. Animals transplanted intramuscularly with 2 X 10(4) viable tumour cells manifested 2 peaks of RE stimulation at 6 and 14 days post-transplantation with a subsequent decline in the phagocytic activity over the 14-30 day period. Increased phagocytic activity as determined by colloid clearance was primarily a reflection of hepatic Küpffer cell hyperphagocytosis while the decline in phagocytic activity was related to a decrease in Küpffer cell function. The initial peak of RE stimulation was associated with an elevation in the blood opsonin level and no significant enlargement of the liver and spleen. In contrast, the second peak of RE stimulation at 14 days was associated with both an elevation in opsonin levels and an associated hepatic and splenic enlargement. The decline in phagocytic activity over the 14-30 day interval was associated with a progressive decline in the plasma opsonic activity, a return of the spleen to its normal size in relationship to the body weight, and a persistent hepatomegaly. These findings suggest that the alterations in macrophage function during tumour growth may be mediated in part by changes in the opsonic or phagocytosis promoting capacity of plasma. Since opsonic protein contributes to the discriminatory capacity of macrophages, it is suggested that changes in the blood opsonin level may condition the anti-tumour capacity of the macrophage system with respect to host defence aginst malignant disease.