title: Interleukin-2-induced lung injury. The role of complement.
abstract: Pulmonary edema and sepsis-like syndrome are grave complications of interleukin-2 (IL-2) therapy. Recent animal studies have suggested IL-2-induced microvascular injury as the underlying mechanism. Since complement factors have been shown to mediate increased vascular permeability in diverse conditions that lead to pulmonary injury and recombinant human IL-2 is known to activate the complement system in patients undergoing IL-2 therapy, we hypothesized that complement factors play a pivotal role in the development of increased vascular permeability after IL-2 treatment. To test this hypothesis, we evaluated the capacity of recombinant soluble human complement receptor type 1 (sCR1, BRL 55730), a new highly specific complement inhibitor, to attenuate IL-2-induced lung injury in the rat. Recombinant human IL-2 (intravenously for 60 minutes) at 10(6) U per rat (n = 4) elevated lung water content (37 +/- 6%, P < .05), myeloperoxidase activity (162 +/- 49%, P < .05), and serum thromboxane B2 (30 +/- 1 pg/100 microL, P < .01) and had no effect on serum tumor necrosis factor-alpha sCR-1 at 30 mg/kg (n = 5), but not at 10 mg/kg (n = 6), attenuated the elevation of lung water content (18 +/- 2%, P < .05) and myeloperoxidase activity (42 +/- 9%, P < .05) but failed to alter serum thromboxane B2 response to IL-2. These data suggest the involvement of complement in the pathogenesis of IL-2-induced pulmonary microvascular injury and point to the potential therapeutic capacity of complement inhibitors in combating this toxic effect of IL-2 therapy.
authors.affiliation: Department of Surgery, Jefferson Medical College, Philadelphia, Pa. 19107-5083.
authors.forename: R
authors.initials: R
authors.lastname: Rabinovici
authors.forename: M D
authors.initials: MD
authors.lastname: Sofronski
authors.forename: P
authors.initials: P
authors.lastname: Borboroglu
authors.forename: A M
authors.initials: AM
authors.lastname: Spirig
authors.forename: L M
authors.initials: LM
authors.lastname: Hillegas
authors.forename: J
authors.initials: J
authors.lastname: Levine
authors.forename: J
authors.initials: J
authors.lastname: Vernick
authors.forename: S M
authors.initials: SM
authors.lastname: Scesney
authors.forename: N
authors.initials: N
authors.lastname: Feuerstein
authors.forename: G
authors.initials: G
authors.lastname: Feuerstein
mesh_terms: D000818:Animals; D002460:Cell Line; D003165:Complement System Proteins / Q000502:physiology*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011951:Receptors, Complement / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013929:Thromboxane B2 / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D007376:Interleukin-2; D011951:Receptors, Complement; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C082885:soluble complement inhibitor 1; D013929:Thromboxane B2; D003165:Complement System Proteins; D009195:Peroxidase; D013936:Thymidine; D007213:Indomethacin