kinin system and kinin antagonists in trauma

Immunopharmacology ELSEVIER

lmmunopharmaculogy 33 (1996) 279-283

The kallikrein/kinin system and kinin antagonists in trauma Timothy C. Rodell Cortech Inc., 6850 N. Broadway, Denver, CO 80221, USA

Keywords: Kallikrein/kinin system; Kinin antagonist: Trauma

Multiple lines of evidence have demonstrated the activation of the kallikrein/kinin system in trauma and have implicated kinins in the inflammatory response to trauma. Andreasson et al. (1989) showed that the kallikrein/kinin system was activated in pulmonary trauma in sheep and that this activation was not blocked by corticosteroids. Carvalho et al. (1988) showed that patients with acute respiratory distress syndrome (ARDS), secondary to either trauma or sepsis, showed evidence of activation of the kallikrein/kinin system when compared to controls without ARDS.

Further, and more direct, evidence of a central role for the kallikrein/kinin system in the systemic response to trauma was provided by Christopher et al. (1994) in a series of experiments performed in rats using the B 2 kinin receptor antagonist, CP-0127. In this study, they showed that in rats subjected to severe soft tissue trauma in a Noble-Collip drum apparatus, the decrease in mean arterial blood pressure seen following removal from the apparatus was blocked in a dose-dependent fashion by CP-0127 (Fig. 1). Superior mesenteric artery (SMA) rings taken from these animals also show a loss of en-

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dothelial mediated relaxation to acetylcholine. This loss of endothelial-mediated vascular reactivity is also blocked in a dose-dependent fashion by CP0127. That the relaxation is mediated by the endothelium is demonstrated by the finding that reactivity to NaNO 2, a non-endothelial mediated vasodilator, is unaffected (Fig. 2). In addition, the infiltration of neutrophils into intestinal tissue as measured by tissue levels of myeloperoxidase (MPO) activity, which is seen in these traumatized animals, is also blocked

by CP-0127 in a dose-dependent fashion (Fig. 3). Finally, survival time was significantly longer in animals treated with CP-0127 (Fig. 4). A study to investigate the effect of CP-0127 in severe multiple trauma in humans is currently ongoing. Similar biochemical mechanisms may be involved in traumatic brain injury (TBI) and other forms of central nervous system (CNS) injury including spinal cord trauma. It has been demonstrated in a series of studies that exogenously administered kinins cause

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vascular leak in the central nervous system, that endogenous kinins in brain tissue can be activated by trauma causing disruption of the blood brain barrier, and that inhibition of the production of kinins by aprotinin and/or soybean trypsin inhibitor (SBTI) blocks vascular leak and brain swelling in response to a cold lesion in rabbits (Unterberg et al., 1984; Unterberg and Baethmann, 1984; Maier-Hauff et al., 1984). Support for these data has been supplied by the demonstration that CP-0127, when administered to rabbits prior to production of a cold lesion, decreases vascular leak as measured by Evan's blue dye leak and also produces a trend toward a decrease in lesion size (Fig. 5E, Whalley, personal communication)• 5000" 0.

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Fig. 6. (A) Kininogen levels in the fight hemisphere of rat brains following fluid percussion brain injury. The injury device is implanted over the right hemisphere. ~ P < 0.05 vs. sham control; b p < 0.05 vs. 10 min postinjury; c p < 0.05 vs. 15 h postinjury. n - 4 for each group. (B) Kininogen levels in the left hemisphere of rat brains following percussion brain injury. The injury device is implanted over the fight hemisphere, a p < 0.05 vs. sham control, n = 4 - 9 for each group. Note that there is some secondary increase in kininogen at 15 h after injury.

T.C. Rodell / lmmunopharmacology 33 (1996) 279-283

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Fig. 7. Effect of the kinin antagonist on the cerebral response to neural trauma, arterioles on one side of the brain were pretreated topically with the kinin receptor antagonist ([]), while arterioles under the contralateral cranial window received only the vehicle for the kinin antagonist ( • ) . T h e antagonist did not affect the preinjury vasoconstrictor response to hyperventilation (HV) but did reduce arteriolar dilatation at 5 min after injury. Additionally, only the antagonist-treated arterioles reacted normally when the animals were again hyperventilated at 1 h after injury ( * P < 0.05). (Reprinted from Ellis et al.: Am J Physiol 1988; 255; H397-H400.)

While cold lesion models may be viewed as somewhat non-specific, Ellis and his colleagues have also shown that kinins are involved in vascular reactivity, eicosanoid production and oxidant production in fluid percussion models in animals and that these effects can also be blocked by a kinin receptor antagonist (Ellis, 1990). Fig. 6A shows the kininogen levels in the directly-injured hemisphere of rat brains following fluid percussion injury while Fig. 6B shows kininogen levels in the contralateral hemisphere. Interestingly, the contralateral hemisphere shows a biphasic response in kininogen levels which could correlate with later occurring events in clinical TBI. Fig. 7 shows that a kinin antagonist decreases the pial arteriolar dilation seen following fluid percussion injury and interestingly also restores the normal response to hyperventilation. Furthermore, in spinal cord trauma, Xu et al. (1991) have also shown that kininogen levels are increased following trauma, suggesting a role for the kallikrein/kinin system in this form of injury as well. These data and others led us to undertake a pilot study of the effect of the B 2 antagonist, CP-0127, in

traumatic brain injury in humans. This study (Narotam et al., 1995), which was completed in September 1994, enrolled a total of 20 patients in a randomized placebo-controlled trial. Inclusion criteria included focal head injury with evidence of a cerebral contusion on CT scan and a Glasgow Coma Score > 9 and < 14. Patients who were treated with CP-0127 showed lower peak ICP levels as well as mean ICP levels, had fewer deteriorations in neurologic function as measured by Glasgow Coma Score (GCS), and required less surgery for evacuation of their contusions (seven out of nine patients in placebo versus one out of eleven patients treated with CP0127, P = 0.005). No safety problems were seen. These results are currently being confirmed in a follow on multi-center trial.

Summary These data and others indicate that the kallikrein/kinin system is activated in both systemic and central nervous system trauma and that specific kinin antagonists are active in animal models of

T.C. Rodell / Immunopharmacology 33 (1996) 279-283 s y s t e m i c a n d C N S t r a u m a . In a d d i t i o n , p r e l i m i n a r y data in h u m a n s s u g g e s t that k i n i n a n t a g o n i s t s m a y h a v e a role in the m a n a g e m e n t o f t r a u m a t i c b r a i n injury. Clearly, f u r t h e r studies in t h e s e i n d i c a t i o n s are indicated.

References Andreasson S, Smith L, Aasen AO, Anderson OK, Risberg B. Proteolytic and lysosomal enzymes in acute trauma-induced lung injury in sheep. Acta Chir Scand 1989; 1-6. Carvalho AC, DeMarinis S, Scott CF, Silver LD, Schmaier AH, Colman RW. Activation of the contact system of plasma proteotysis in the adult respiratory distress syndrome. J Lab Clin Med. 1988; 112: 270-277. Christopher TA, Ma X-L, Gauthier TW, Lefer AM. Beneficial actions of CP-0127, a novel bradykinin receptor antagonist, in murine traumatic shock. Am J Physiol (Heart Circ Physiol 35). 1994; 266: H867-H873.

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Unterberg A, Baethmann AJ. The kallikrein-kinin system as mediator in vasogenic brain edema. Part 1: Cerebral exposure to bradykinin and plasma. J Neurosurg 1984; 61: 87-96. Maier-Hauff K, Baethmann A J, Lange M, Schiirer L, Unterberg A. The kallikrein-kinin system as mediator in vasogenic brain edema. Part 2: Studies on kinin formation in focal and perifocal brain tissue. J Neurosurg 1984; 61: 97-106. Unterberg A, Dautermann C, Baethmann A, MiJller-Esterl W. The kallikrein-kinin system as mediator in vasogenic brain edema. Part 3: Inhibition of the kallikrein-kinin system in traumatic brain swelling. J Neurosurg 1984; 61: 87-96. Ellis EF. Initiation of eicosanoid and free radical formation following brain injury: the role of the kallikrein-kinin system, in Braquet P, Robinson LP (eds.). New Trends in Lipid Mediators Research. Basel: Karger. 1990; 129-145. Xu J, Hsu CY, Junker H, Chao S, Hogan EL, Chao J. Kininogen and kinin in experimental spinal cord injury. J Neurosurg 1991; 57: 975-980. Narotam PK, Nadvi SS, Bhoola KD, Rodell TC, van Dellen JR, Traumatic brain contusions: a clinical role for a kinin antagonist in reducing secondary brain swelling. 63rd Annual Meeting of the American Association of Neurological Surgeons. 1995; 733.