Eric S. Kalter

Rosmarinic acid inhibits external oxidative effects of human polymorphonuclear granulocytes

Introduction Ingestion of bacteria by human polymorphonuclear leukocytes (PMN) and perturbation of the cell membrane initiates a burst of oxygen consumption. This metabolic burst results in the formation of highly toxic oxygen species which play an important role in the PMN defense mechanisms [I]. As a consequence of PMN stimulation, these toxic oxygen products are released into the direct environment and tissue damage may occur at sites of infection and inflammation. The experimental drug Rosmarinic acid (Nattermann, Cologne, FRG) was shown to possess anti-inflammatory properties in an animal model of Adult Respiratory Distress Syndrome and multiple organ inflammation, based on complement induced granulocyte activation [2]. Therefore it was of interest to study in vitro the effects of Rosmarinic acid on a number of human PMN functions, related to host defense mechanisms and the production of oxygen radicals.

Effects of methylprednisolone on hemodynamics, arteriovenous oxygen difference, P50, and 2,3 DPG in bacterial shock: a preliminary study.

Ten patients with bacteremia and perfusion failure were given methylprednisolone sodium succinate (MPN), 30 mg/kg iv, as adjunctive therapy immediately after initial volume loading to a pulmonary artery wedge pressure (WP) of 12 ± 4 (SD) mm Hg. Hemodynamic and oxygen measurements were obtained before, and for 24 h after MPN. All patients exhibited arterial hypotension (x = 65 ± 17, mm Hg), mental clouding and lactacidemia (x 2.5 ± 0.7, mM/L). Nine patients recovered from shock within 12 h. However, only 4 were hospital survivors. Cardiac index (CI), oxygen delivery index, and lactate increased immediately after MPN from 3.7 ± 0.9 to 3.9 ± 1.0 L/min M2 (p <0.05), 485 ± 143 to 534 ± 143 ml/min M2 (p <0.05), and 2.5 ± 0.7 to 2.8 ± 0.8 mM/L (p = ns), respectively. However, there was a simultaneous decrease in arteriovenous oxygen difference [C(a-v)O2] so that oxygen consumption (Vo2) was unchanged. WP decreased immediately after MPN to 10.4 ± to 4.9 mm Hg (p = ns) accompanied by decreases in pulmonary and systemic vascular resistance. P50 and erythrocyte 2,3 diphosphoglycerate (2,3 DPG) were little affected for 12 h (in vitro P50 25.0 ± 2.1 to 25.9 ± 1.3 mm Hg, and 2,3 DPG 12.6 ± 3.7 to 15.4 ± 2.4 γm/g Hb (p = ns). For the patients who recovered from shock there were additional small (p = ns) increases in P50 and 2,3 DPG by 24 h. These were not accompanied by an increase in C(a-v)o2 or Vo2. We conclude that MPN increases cardiac output and O2 delivery in bacterial shock, but these changes do not seem to be associated with increases in systemic oxygen extraction, erythrocyte 2,3 DPG, or P50

Effects of methylprednisolone on P50, 2,3 diphosphoglycerate and arteriovenous oxygen difference in acute myocardial infarction.

In a double-blind randomized study, 30 mg/kg of methylprednisolone sodium succinate (MPN) or 15 mg/kg of mannitol placebo (PL) were infused in 28 patients after acute myocardial infarction. Measurements were obtained immediately before and for 24 hours after the initial infusion. The partial pressure of oxygen at 50% saturation of hemoglobin (P50,) did not change significantly in vitro or in vivo after MPN, whereas 2,3 diphosphoglycerate (2,3 DPG) increased from 13.2 to 14.2 μmol/g Hb (p < 0.05) in the group receiving PL. The arteriovenous oxygen difference (Ca-vO2) remained constant after MPN or PL. The cardiac index (CI) increased after MPN (p < 0.02) associated with an increase in the oxygen consumption index (Ca V 02) from 146 to 170 ml/min/m2 (p < 0.05). These data show that MPN increases CI after acute myocardial infarction, but has no specific effects on P50, 2,3 DPG or Ca-vO2.

Inactivation of kallikrein during sepsis and bacterial shock

The inactivation of kallikrein was studied in plasma samples of 20 patients with uncomplicated sepsis and 32 patients with bacterial shock. The kallikrein inactivation capacity of plasma was measured after addition of purified kallikrein to the samples and was at the upper level of normal during sepsis (112±28% (SD)) and at low normal level during bacterial shock (85±30%,p<0.005). Elimination of α2M in these plasma samples did not significantly influence the results. In agreement with these data we found equally decreased α2M antigen levels to approximately 60% in both patient groups. Of the other inhibitors of kallikrein, ATIII levels were below normal during uncomplicated sepsis (62±21%) and significantly lower during bacterial shock (41±20%,p<0.001). In contrast, CIINH levels were increased during uncomplicated sepsis to twice the normal level, both when measured immunochemically (ag) (190±57%) and when measured immunochemically (ag) (190±57%) and when measured functionally (192±87%) and this was significantly higher as compared to the group with bacterial shock (CIINHag 125±44%, CIINH 110±46%).We conclude that CIINH plays a major role in the inactivation of kallikrein during sepsis.

The effect of antisera on the induction of shock byE. coli

Introduction The inflammatory response to bacterial invasion depends on the activation of host defence mechanisms by surface components of the bacterial cell wall, especially the activation of the complement system, opsonization and phagocytosis. Some bacterial strains contain cell wall structures which increase their resistance to these processes. E. coli strains with K capsular antigens have been associated with increased virulence because of their higher degree of involvement in invasive infections and their resistance to phagocytosis [1]. The capsular antigen inhibits complement activation and opsonization in normal human serum, and the early phase of experimentally induced hypotension in rats [2, 31. We demonstrated that antibodies enhanced opsonization of these strains in normal human serum and were protective in a mouse animal model [4]. In the present study, we investigated the effect of prior administration of antibodies on the induction of hypotension by E. coli strains in rats.