Complement-dependent accumulation and degradation of platelets in the lung and liver induced by injection of lipopolysaccharides

Abstract

We found unique behaviors among platelets within a few minutes of the intravenous injection of lipopolysaccharide (LPS) into mice. Platelets accumulated primarily in the liver at lower doses of LPS, but at higher doses they accumulated largely in the lungs. When the platelets accumulated in these organs were degraded, there was a rapid anaphylactoid shock. The platelet response depended on the strain of mouse and on the source of LPS. Of various LPSs tested, the LPS from the smooth type of Klebsiella O3 (KO3-S LPS) was the most potent at inducing the platelet response and shock. K-76 monocarboxylic acid, an inhibitor of complement C5, effectively prevented the KO3-S LPS-induced degradation (but not accumulation) of platelets and the ensuing rapid shock in BALB/c mice. Moreover, in DBA/2 mice (which are deficient in complement C5), platelets accumulated in the lungs and liver in response to KO3-S LPS but soon returned to the circulation without degradation, and there was no rapid shock. The LPS from the rough type of KO3 induced an accumulation of platelets in the liver and lungs but not a degradation of platelets. On the basis of these results and those reported by other investigators, we propose that in the platelet response to LPS, the lectin pathway to form C3 convertase from C4 and C2 is involved in the rapid accumulation of platelets in the liver and lungs and that the pathway from C5 to C9 is involved in the destruction of platelets and the consequent anaphylactoid shock.

FIG. 1

Time course of changes in 5HT and platelet levels induced by the LPSs of KO3-S and KO3-R in BALB/c mice. After injection of each LPS at a dose of 2 mg/kg, blood and tissues were taken at the indicated times. Each value is the mean ± SD from four mice. ∗, P <0.01 versus the KO3-R group.

FIG. 2

Dose dependence of 5HT and platelet responses to KO3-S LPS in BALB/c mice. The indicated doses of LPS were injected into mice, and blood and tissues were taken 4 min after the injection. Each value is the mean ± SD from four mice. ∗, P <0.01 versus dose 0.

FIG. 3

Effects of K-76, an inhibitor of complement C5, on 5HT and platelet responses to KO3-S LPS in BALB/c mice. LPS (1 mg/kg) was injected 1 h after an intraperitoneal injection of K-76 (100 mg/kg). Blood and tissues were taken 5 and 15 min after the injection of the LPS. K-76 itself did not alter the levels of 5HT (data not shown). Each value is the mean ± SD from four mice.

FIG. 4

5HT and platelet responses to KO3-S LPS in DBA/2 mice. Blood and tissues were taken at the indicated times after the injection of LPS (2 mg/kg). Each value is the mean ± SD from four mice. ∗, P <0.01 versus time 0.

FIG. 5

Dose dependence of 5HT and platelet responses to KO3-S LPS in DBA/2 mice. The indicated doses of LPS were injected into mice, and blood and tissues were taken 4 min after the injection. Each value is the mean ± SD from four mice. It should be noted that the 5HT and platelet responses in the liver reached their maximum at 0.1 mg/kg and, at this dose, there was no response in the lungs. ∗, P <0.01 versus dose 0.

FIG. 6

Hypothetical pathway for the LPS-induced accumulation and degradation of platelets in the lungs and liver. In this tentative scheme, LPS is assumed to bind to MBP-MASP complex and a consequent complex stimulates MBP receptors on platelets and vascular endothelial (ET) cells in the liver and lungs. The LPS-MBP-MASP complex also activates the complement system. The pathway to form C3 convertase from C4 and C2 may be responsible for the accumulation of platelets in the liver and lungs. The pathway from C5 to C9 may be involved in the destruction of platelets, and the O antigen polysaccharide region of KO3-S LPS may be important in this step. The degradation of platelets in the liver and lungs and the release of their contents, including serotonin (5HT), lead rapidly to shock. When the complement system is not activated, or if its activation is insufficient, the platelets accumulated in the lungs and liver return to the circulation without degradation or with only slight damage. The platelets that suffer slight damage may be removed from the circulation by the spleen.