Lung Vascular Injury after Administration of Viable Hemolysin-formingEscherichia coliin Isolated Rabbit Lungs

Abstract

Escherichia coli hemolysin, a transmembrane pore-forming exotoxin, is considered an important virulence factor. In the present study, the possible significance of hemolysin production was investigated in a model of septic lung failure through infusion of viable bacteria in isolated rabbit lungs; 10(4) to 10(7) E. coli/ml perfusate caused a dose- and time-dependent appearance of hemolysin, accompanied by release of potassium, thromboxane A2, and PGI2 into the perfusate. Concomitantly, marked pulmonary hypertension developed. Inhibitor studies suggested that the pressor response was predominantly mediated by pulmonary thromboxane generation. Administration of hemolysin-forming E. coli additionally caused a protracted, dose-dependent increase in the lung capillary filtration coefficient, followed by severe edema formation. The permeability increase was independent of lung prostanoid generation. An E. coli strain that releases an inactive form of hemolysin completely failed to provoke the described biophysical and biochemical responses. Preapplication of 2 x 10(8) human granulocytes was without effect in the present experimental model. We conclude that the hemolysin produced by low numbers of E. coli organisms can provoke thromboxane-mediated pulmonary hypertension and severe vascular leakage. E. coli hemolysin and, possibly, other related cytolysins may thus contribute directly to the pathogenesis of acute respiratory failure under conditions of sepsis or pneumonia.

Release of Leukotriene A4 Leukotriene B4 from Human Polymorphonuclear Leukocytes

“…Grimminger and co-workers (13)(14)(15) showed that perfusion and activation of PMNL in the isolated lung of the rabbit resulted in the production of significantly increased amounts of cysteinyl leukotrienes, with respect to activation of PMNL alone. Similar results were obtained in our laboratory using a PMNL-perfused isolated rabbit heart (16,18).…”

“…Upon cell activation, significant amounts of LTB 4 and its -oxidized metabolites 20-hydroxy-and 20-carboxy-LTB 4 are released into the extracellular milieu together with nonenzymatic breakdown products of LTA 4 , namely ⌬ 6 -trans-LTB 4 isomers and 5,6-dihydroxyeicosatetraenoic acids (5,6-diHETEs) (10 -12). Recent studies in complex organ systems (13)(14)(15)(16)(17)(18) showed that perfusion of PMNL in the isolated lung or heart of the rabbit only caused a significant increase in the production of cysteinyl leukotrienes when PMNL were activated during the perfusion process. These data suggest that transcellular biosynthesis of cysteinyl leukotrienes might indeed be of physiopathological relevance when tight cell-cell interactions occur, such as during adhesion and diapedesis of PMNL through the microvascular endothelium of a functioning organ system.…”

Initial Characterization of the Hemolysin Stachylysin fromStachybotrys chartarum

“…Many bacterial hemolysins create pores not only in RBCs, but also in the membranes of nucleated cells (e.g., neutrophils, monocytes, and endothelial cells) (2,10,20), and can affect the aggregation of platelets (12). These hemolysin-mediated responses affect the pathophysiology of the host.…”

Stachylysin May Be a Cause of Hemorrhaging in Humans Exposed to Stachybotrys chartarum

“…Hemolysins have been shown to have great significance in the virulence of many bacteria (1,2,3,11,19,24,25,29,33) and of the few fungal pathogens for which they have been examined (6,7,8,20,26,27). Many of these hemolysins damage vascular tissue, resulting in hemorrhaging.…”