Morphological Basis of Pulmonary Edema in Mice with Cytokine-Induced Vascular Leak Syndrome

Abstract

Patients injected systemically with recombinant human interleukin-2 (rhIL-2) for treatment of solid tumor develop a vascular leak syndrome (VLS), characterized mainly by pulmonary edema whose pathogenesis is unknown. We have examined the structure of pulmonary vessels in mice with severe VLS induced by systemic injections of rhIL-2 and recombinant human interferon-alpha-A/D (rhIFN-alpha), which has a synergistic effect with IL-2. The pulmonary edema was associated with lesions of venous and capillary endothelia, alveolar basement membrane, and type I epithelial cells. These changes were more severe and diffuse than those seen in mice systemically injected with rhIL-2 alone, and in beige mice (deficient in NK cells and certain enzymes of polymorphonuclear leukocytes) injected with rhIL-2 and rhIFN-alpha. The endothelial lesions were comparable to those seen when leukocytes activated by cytokines react with activated endothelial cells in vitro, or at the site of injection of cytokines in vivo. The observations are in agreement with the interpretation that the severe lesions occurring in mice systemically injected with rhIL-2 with rhIFN-alpha result from the interaction of leukocytes with the endothelium. The results confirm the validity of previous studies performed in vitro or in animals injected intradermally with cytokines and extend their significance.

Endothelial cells are activated by cytokine treatment to kill an intravascular parasite, Schistosoma mansoni, through the production of nitric oxide.

“…Alternatively, such hostile conditions may make it attractive for the parasite to attempt to escape from its intravascular location. Cytokine treatment has been shown to increase EC "leakiness" (22), a fact that may not only contribute to perivascular inflammation but also promote the exodus of some larvae. In addition, because NO may also be toxic to the cells which produce it (23), selfdestruction of activated ECs could facilitate the escape of some larvae into the alveolar spaces, from which they cannot return to the bloodstream and where they may become the target of inflammatory reactions with activated macrophages.…”

Positive and Negative Regulation by NK Cells in Cancer

“…58–60 IL-15 is an alternative to IL-2 and is potentially superior due to the lack of the side effects associated with IL-2 and no activation of Tregs as seen with IL-2 administration. 61,62 Combined IL-2 and anti-CD25 can also reduce Treg activation and enhance anti-tumor responses.…”

Noncardiogenic Pulmonary Edema: An Unusual and Serious Complication of Anticancer Therapy

“…Initial preclinical studies suggested that microvasculature damage, causing a generalized increase of vascular permeability to albumin, was the basic mechanism of rIL-2-induced NCPE [25]. Subsequent studies went into more detail and associated the systemic administration of rIL-2 with lesions of venous and capillary endothelia, alveolar basement membrane, and type I epithelial cells in animals, while leukocyte or platelet activation, generation of free radicals, and activation of the complement system have also been suggested to be involved in its pathogenesis [92][93][94][95][96][97]. Despite a widening evidence of the involvement of various cytokines released by activated lymphoid cells in the pathogenesis of rIL-2-induced NCPE, the exact mechanism of the damaging events that drive this clinical syndrome remain unclear [23,33].…”