Clinical and angiographic features and stroke types in adult moyamoya disease.

BACKGROUND AND PURPOSE: This study was conducted to elucidate the association between clinical and angiographic characteristics and stroke types in adult Moyamoya disease that has been rarely evaluated. MATERIALS AND METHODS: We analyzed the clinical and radiologic data obtained from a retrospective adult Moyamoya disease cohort with acute strokes, which were classified into 7 categories: large-artery infarct, hemodynamic infarct, perforator infarct, deep intracerebral hemorrhage, lobar intracerebral hemorrhage, intraventricular hemorrhage, and SAH. With conventional angiography, which was performed in the hemispheres with acute strokes, the Suzuki angiographic stage, intracranial aneurysm, major artery occlusion, and collateral vessel development were confirmed within 1 month of stroke onset. RESULTS: This study included 79 patients with acute ischemic stroke and 96 patients with acute hemorrhagic stroke. The angiographic stage had a strong tendency to be more advanced in the hemorrhagic than the ischemic patients (P = .061). Intracranial aneurysms were more frequently found in the hemorrhagic than ischemic or control hemispheres (P = .002). Occlusions of the anterior cerebral artery and development of fetal-type posterior cerebral artery were more frequently observed in the hemorrhagic than the ischemic (P = .001 and .01, respectively) or control hemispheres (P = .011 and .013, respectively). MCA occlusion (P = .039) and collateral flow development, including the ethmoidal Moyamoya vessels (P = .036) and transdural anastomosis of the external carotid artery (P = .022), occurred more often in the hemorrhagic than the ischemic hemispheres. Anterior cerebral artery occlusion occurred more frequently in patients with deep intracerebral hemorrhage or intraventricular hemorrhage than with lobar intracerebral hemorrhage (P = .009). CONCLUSIONS: In adult Moyamoya disease, major artery occlusion and collateral compensation occurred more often in the hemorrhagic than in the ischemic hemispheres. Thus, anterior cerebral artery occlusion with or without MCA occlusion and intracranial aneurysms may be the main contributing factors to hemorrhagic stroke in adult patients with Moyamoya disease.

Therapeutic results of intra-arterial thrombolysis after full-dose intravenous tissue plasminogen activator administration.

BACKGROUND AND PURPOSE: IV administration of tPA is accepted as a standard treatment for acute cerebral ischemia, but the clinical outcomes cannot be guaranteed in patients who are not recanalized after IV-tPA and in those who are not eligible for IV-tPA. In this study, outcomes from groups of patients treated with additional IA thrombolytic therapy with the use or omission of IV-tPA administration were compared. MATERIALS AND METHODS: IA thrombolytic therapy (thrombolytic agents combined with mechanical intervention) was attempted in those patients who were not eligible for IV-tPA and who showed continuous major vessel occlusion after IV-tPA. Sixty-three patients were divided into 2 groups: a tPA group (n = 29, IA thrombolysis after IV-tPA) and a non-tPA group (n = 34, IA thrombolysis without IV-tPA). These groups were subdivided according to match or mismatch DWI/PWI after MR imaging. Treatment results were compared by recanalization rate, clinical outcome, mortality, and ICH rate. RESULTS: The recanalization rate was 79.3% in the tPA group and 55.9% in the non-tPA group (χ(2) test, P < .05). Subgroup analysis between DWI/PWI mismatch in the tPA group and DWI/PWI mismatch in the non-tPA group also showed no statistical difference in recanalization rate, favorable clinical outcome, and mortality (χ(2) test, P > .05), but the significant ICH rate was high in the tPA group (χ(2) test, P < .05). CONCLUSIONS: Additional IA thrombolytic treatment after full-dose IV-tPA administration might be an acceptable treatment option for patients with DWI/PWI mismatch.

Clinical and radiographic results of unilateral transpedicular balloon kyphoplasty for the treatment of osteoporotic vertebral compression fractures.

INTRODUCTION: Most previous reports indicate that traditional bilateral kyphoplasty improves patient function and restores height of collapsed vertebral bodies, but limited data about the effects of unilateral kyphoplasty on clinical and radiological outcome are available. MATERIAL AND METHODS: One hundred five patients were treated by unilateral kyphoplasty between January 2004 and December 2006. These patients underwent 105 operations to treat 132 vertebral compression fractures between T8 and L5. Sagittal alignment was analyzed from standing radiographs. Clinical outcomes were determined by comparison of preoperative and postoperative data from patient-reported index (visual analogue pain scale score). Radiographs were assessed as to percent vertebral collapse, vertebral height restoration and local kyphosis correction. RESULTS: Mean length of follow-up was 15.3 months (range 3-36 months); improved height 2.3 and 4.0 mm in the anterior and medial columns, respectively (P > 0.05); Cobb angle increased 3.0 degrees (P < 0.05), visual analogue pain scale score improved from 8.7 +/- 1.4 before surgery to 2.3 +/- 0.9 (P < 0.05); no adverse medical or procedural complications; 6.8% (9/132) cement leakage rate. CONCLUSION: Unilateral transpedicular kyphoplasty improves physical function, reduces pain, and may correct kyphotic deformity associated with vertebral compression fractures. This result shows comparable to traditional bilateral kyphoplasty procedure.

Significance of temperature difference between cerebral cortex and axilla in patients under hypothermia management.

It is believed that the brain temperature is about 1 degree C higher than the other peripheral temperature. But the result has been mostly obtained in normothermia patients. The objective of this study was to evaluate whether the brain temperature is still higher than the axillary one in the hypothermia patients. Sixty-three patients who underwent craniotomy with implantation of the thermal diffusion thermometer were included in this study. Fifty-four patients were in normothermia and nine patients were managed with mild to moderate hypothermia (about 32 degrees C). The temperature of the cerebral cortex and axilla was measured simultaneously every 2 hours. 1900 paired sample data were collected and analyzed. The temperature difference between the cerebral cortex and the axilla was 1.04 +/- 0.67 degrees C in normothermia patients and 0.91 +/- 0.84 degree C in hypothermic patients. The temperature difference has no statistical significance between the two groups (unpaired t-test, P > 0.05). Our results demonstrate that the brain temperature in the patients under hypothermia management appears to be still about 1 degree C higher than the axilla throughout the study period almost in the same fashion as in normothermia patients.

Cerebral activation and distribution of inducible hsp110 and hsp70 mRNAs following focal ischemia in rat.

A potential function for inducible heat shock protein 70 (hsp70i) expression in the pathophysiology of ischemic brain has been well documented. The recently cloned hsp70 superfamily member, hsp110, was shown to be highly expressed in the brain and suggested to have a similar functional property as members of the hsp70 family. In this study, as an initial step to probe for its physiological significance in the ischemic brain, cerebral activation and distribution of hsp110 mRNA was comparatively evaluated with that of hsp70i mRNA by in situ hybridization. A rat focal cerebral ischemia model was employed to examine the distribution and localization of hsp110 and hsp70i mRNAs in both affected (ipsilateral) and unaffected (contralateral) hemispheres of the same animal. Our results demonstrated a significant accumulation of hsp110 as well as hsp70i mRNAs following ischemia; although the magnitude and kinetics of induction differ slightly, spatial expression profiles of hsp110 and hsp70i mRNAs were highly correlated in the affected region. In control brain, limited hybridization signal was observed with 3'-untranslated region (UTR) containing hsp110 probe, suggesting a possible existence of inducible hsp110 and a selective recognition of our 3'-UTR containing probe for the inducible hsp110 mRNA species. Subsequent 2D western analysis with Hsp110 specific Ab was consistent with our view, which resolved constitutive and inducible immunostained spots in rat ischemic brain. Considering a regulatory similarity as well as previously documented structural and functional similarities between hsp110 and hsp70i, we propose that coordinated cerebral activation of hsp110 and hsp70i is likely to be of significant relevance in the context of pathophysiology of ischemic brain. Further study is required to characterize the genetic and biochemical nature of rat inducible hsp110 identified in the current study.

Neuroprotection by LY341122, a novel inhibitor of lipid peroxidation, against focal ischemic brain damage in rats.

LY341122 (2-(3, 5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-methylethylaminomethyl-ph enylox y)ethyl)oxazole) is a potent inhibitor of lipid peroxidation which has been shown to protect against global ischemia and traumatic brain injury in rats. The purpose of this study was to examine the effect of LY341122 on ischemic injury in a highly reproducible model of focal cerebral ischemia in rats. Male Sprague-Dawley rats were anesthetized with halothane and subjected to 120 min of temporary middle cerebral artery occlusion by retrograde insertion of an intraluminal nylon suture coated with poly-L-lysine. The drug (LY341122, n=19) or vehicle (phosphate-buffered saline (PBS), n=10) was administered i.v. (as a 5 or 10 mg/kg bolus followed by a 5 or 10 mg/kg/h infusion for 20 h, respectively, starting 1 or 2 h after the onset of middle cerebral artery occlusion). Neurological status was evaluated during middle cerebral artery occlusion (60 min) and daily for 3 days thereafter. Three days after ischemia, brains were perfusion-fixed and infarct volumes and brain edema were determined. LY341122 significantly improved the neurological score compared to vehicle at 24, 48 and 72 h after middle cerebral artery occlusion. Treatment with LY341122 significantly reduced total infarct volume in all treated groups compared to vehicle rats. Cortical infarct volume was significantly reduced by LY341122 treatment in the 10 mg/kg (1 h) and LY341122 10 mg/kg (2 h) groups compared to vehicle rats (14.7+/-9.5 vs. 106.8+/-20.9 mm(3), and 36.9+/-20.1 vs. 106. 8+/-20.9 mm(3), respectively (mean+/-S.E.M.)). Striatal infarct volume was also significantly reduced by treatment with LY341122 in the 10 mg/kg (1 h) group compared to vehicle (23.7+/-3.4 vs. 68. 2+/-6.7 mm(3)). These results demonstrate the neuroprotective efficacy of LY341122 in focal cerebral ischemia.

Comparative neuroprotective efficacy of prolonged moderate intraischemic and postischemic hypothermia in focal cerebral ischemia.

OBJECT: The purpose of this study was to compare the effects of prolonged hypothermia on ischemic injury in a highly reproducible model of middle cerebral artery (MCA) occlusion in rats. METHODS: Male Sprague-Dawley rats were anesthetized with halothane and subjected to 120 minutes of temporary MCA occlusion by retrograde insertion of an intraluminal nylon suture coated with poly-L-lysine through the external carotid artery into the internal carotid artery and the MCA. Two levels of prolonged postischemic cranial hypothermia (32 degrees C and 27 degrees C) and one level of intraischemic cranial hypothermia (32 degrees C) were compared with the ischemic normothermia (37 degrees C) condition. Target cranial temperatures were maintained for 3 hours and then gradually restored to 35 degrees C over an additional 2-hour period. The animals were evaluated using a quantitative neurobehavioral battery of tests before inducing MCA occlusion, during occlusion (at 60 minutes postonset in all rats except those in the intraischemic hypothermia group), and at 24, 48, and 72 hours after reperfusion. The rat brains were perfusion fixed at 72 hours after ischemia, and infarct volumes and brain edema were determined. Both intraischemic and postischemic cooling to 32 degrees C led to similar significant reductions in cortical infarct volume (by 89% and 88%, respectively) and total infarct volume (by 54% and 69%, respectively), whereas postischemic cooling to 27 degrees C produced lesser reductions (64% and 49%, respectively), which were not statistically significant. All three hypothermic regimens significantly lessened hemispheric swelling and improved the neurological score at 24 hours. The authors' data confirm that a high degree of histological neuroprotection is conferred by postischemic cooling to 32 degrees C, which is virtually equivalent to that observed with intraischemic cooling to the same level. CONCLUSIONS: These results may be relevant to the design of future clinical trials of therapeutic hypothermia for acute ischemic stroke.

Ventricular pressure monitoring during bilateral decompression with dural expansion.

OBJECT: The management of massive brain swelling remains an unsolved problem in neurosurgery. Despite newly developed medical and pharmacological therapy, the rates of mortality and morbidity caused by massive brain swelling remain high. According to many recent reports, surgical decompression with dural expansion is superior to medical management in patients with massive brain swelling. To show the quantitative effect of decompressive surgery on intracranial pressure (ICP), the authors performed a ventricular puncture and measured the ventricular ICP continuously during decompressive surgery and the postoperative period. METHODS: Twenty patients with massive brain swelling who underwent bilateral decompressive craniectomy with dural expansion were included in this study. In all patients, ventricular puncture was performed at Kocher's point on the side opposite the massive brain swelling. The ventricular puncture tube was connected to the continuous monitor via a transducer device. The ventricular pressure was monitored continuously, during the bilateral decompressive procedures and postoperative period. The initial ventricular ICP was variable, ranging from 16 to 65.8 mm Hg. Immediately after the bilateral craniectomy, the mean ventricular ICP decreased to 50.2+/-16.6% of the initial ICP (range 5-51.5 mm Hg). Additional opening of the dura decreased the mean ICP by an additional 34.5% and reduced the ventricular pressure to 15.7+/-10.7% of the initial pressure (range 0-15 mm Hg). Ventricular pressure measured postoperatively in the neurosurgical intensive care unit was lowered to 15.1+/-16.5% of the initial ICP. The ventricular ICP trend in the first 24 hours after decompressive surgery was an important prognostic factor; if it was greater than 35 mm Hg, the mortality rate was 100%. CONCLUSIONS: Bilateral decompression with dural expansion is an effective therapeutic modality in the control of ICP. To obtain favorable clinical outcomes in patients with massive brain swelling, early decision making and proper patient selection are very important.

Anterior thalamoperforating artery aneurysm associated with internal carotid artery occlusion: case report.

OBJECTIVE AND IMPORTANCE: We describe a rare case of a ruptured distal anterior thalamoperforating artery aneurysm associated with right internal carotid artery occlusion. CLINICAL PRESENTATION: A 59-year-old woman experienced sudden occipital headache, vomiting, and subsequent coma as a result of massive intraventricular hemorrhage. An initial angiogram revealed only an occlusion of the right internal carotid artery just distal to the posterior communicating artery. Repeat angiography 1 month later, however, revealed a saccular aneurysm at a distal anterior thalamoperforating artery in addition to the occlusion of the internal carotid artery. INTERVENTION: We approached this aneurysm through the right temporal horn after opening the ambient cistern. The aneurysm, which was located in the brain parenchyma just medial to the temporal horn, was successfully resected. CONCLUSION: This rare aneurysm probably developed as a result of hemodynamic stress on the anterior thalamoperforating artery after occlusion of the internal carotid artery and/or secondary to chronic hypertension.

Neuroprotective effect of high-dose albumin therapy against global ischemic brain injury in rats.

The purpose of this study was to determine whether treatment with high-dose human serum albumin (HSA) would offer protection in a model of high-grade transient forebrain ischemia. Twenty-six fasted Wistar rats underwent bilateral common carotid artery occlusion and severe hypotension (50 mmHg) for 10 min. The agent (25% HSA) or vehicle (0.9% NaCl) was administered i.v. 5 min after termination of ischemia. HSA-treated rats showed significantly improved neurological deficits throughout a 7-day survival period. Histologically, HSA-treated rats showed 2.4- to 5.3-fold increases in numbers of surviving CA1 hippocampal pyramidal neurons compared to saline-treated animals. These results document that high-dose albumin therapy instituted 5 min after global ischemia significantly improves neurological score and reduces histological damage.

The acute ischemic penumbra: topography, life span, and therapeutic response.

Recent advances in computerized image-averaging, used in conjunction with refined techniques for engendering highly reproducible rodent models of focal ischemia, now make it possible to derive topographically precise, quantitative descriptors of the ischemic penumbra--its localization, lifespan, metabolic and hemodynamic features, and responses to therapy. Physiologically monitored normothermic rats received 2-h middle cerebral artery occlusion (MCAo) by means of a poly-L-lysine-coated intraluminal suture. In matched groups, local cerebral blood flow (LCBF) or glucose utilization (LCMRglc) were measured autoradiographically at either 2-h MCAo or at 1-h recirculation and were correlated on a pixel-by-pixel basis with histopathological infarction after 3-day survival. A large, consistent ischemic penumbra (defined as LCBF 20-40% of control) surrounded the core (0-20% of control). Penumbral LCMRglc at 2-h MCAo was near-normal, and its metabolism/flow ratio was elevated 4-fold above normal. By 1-h recirculation, however, LCMRglc throughout the prior zone of ischemia was depressed. Infarctive histopathology was precisely determined by the antecedent LCBF decrement during ischemia: 70% and 89% of infarcted pixels had antecedent LCBF values below the upper-core and upper-penumbral ranges, respectively, at 2-h MCAo. High-dose albumin therapy at the onset of recirculation dramatically attenuated cortical infarction and brain edema and appeared, by LCBF analysis at 1-h recirculation, to increase postischemic LCBF primarily in the former penumbra.

Posttreatment with high-dose albumin reduces histopathological damage and improves neurological deficit following fluid percussion brain injury in rats.

We have recently shown that high-dose human serum albumin (HSA) therapy confers marked histological protection in experimental middle cerebral artery occlusion. Thus, the purpose of this study was to determine whether treatment with high-dose HSA would protect in a rat model of traumatic brain injury (TBI). Twenty-four hours prior to TBI, the fluid percussion interface was positioned parasagittally over the right cerebral cortex. On the following day, fasted rats were anesthetized with 3% halothane, 70% nitrous oxide, and 30% oxygen and received right parieto-occipital parasagittal fluid-percussion injury (1.5-2.0 atm). Cranial and rectal temperatures were monitored throughout the experiment and held at normothermic levels (36.5-37.5 degrees C) by a warming lamp above the animal's head. The agent (25% human serum albumin, HSA) or vehicle (sodium chloride 0.9%) was administered i.v. (1% of body weight) 15 min after trauma. Behavioral function was evaluated in all rats before and after TBI (at 2 h, 24 h, 48 h, 72 h, and 7 days). Neurological function was graded on a scale of 0-12 (normal score = 0; maximal score = 12). Seven days after TBI, brains were perfusion-fixed, coronal sections at various levels were digitized, and contusion areas in the superficial, middle and deep layers of cortex and in the underlying fimbria were measured. HSA significantly improved the neurological score compared to saline at 24 h, 72 h, and 7 days after TBI (6.0 +/- 0.6 [albumin] versus 8.4 +/- 0.5 [saline]; 3.6 +/- 0.7 versus 6.8 +/- 1.0; and 2.6 +/- 0.6 versus 5.7 +/- 0.8, respectively; p < 0.05). HSA therapy also significantly reduced total contusion area (0.89 +/- 0.2 versus 1.82 +/- 0.3 mm2; p = 0.02). Our findings document that high-concentration albumin therapy instituted 15 min after trauma significantly improves the neurological score and reduces histological damage. We believe that this pharmacological agent may have promising potential for the clinical treatment of brain injury.

Diffusion-weighted magnetic resonance imaging confirms marked neuroprotective efficacy of albumin therapy in focal cerebral ischemia.

BACKGROUND AND PURPOSE: We have recently shown high-dose human serum albumin therapy to confer marked histological protection in experimental middle cerebral artery occlusion (MCAo). We have now used diffusion-weighted magnetic resonance imaging (DWI) in conjunction with morphological methods to expand our understanding of this therapeutic approach. METHODS: Physiologically controlled Sprague-Dawley rats received 2-hour MCAo by the modified intraluminal suture method. Treated rats received 25% human serum albumin solution (1% by body weight) immediately after the MCA was reopened. Vehicle-treated rats received saline. Computer-based image averaging was used to analyze DWI data obtained 24 hours after MCAo and light-microscopic histopathology obtained at 3 days. In a matched series, plasma osmolality and colloid oncotic pressure, as well as brain water content, were determined. RESULTS: Albumin therapy, which lowered the hematocrit on average by 37% and raised plasma colloid oncotic pressure by 56%, improved the neurological score throughout the 3-day survival period. Within the ischemic focus, the apparent diffusion coefficient (ADC) computed from DWI data declined by 40% in vehicle-treated rats but was preserved at near-normal levels (8% decline) in albumin-treated rats (P<0.001). Albumin also led to higher ADC values within unlesioned brain regions. Histology revealed large consistent cortical and subcortical infarcts in vehicle-treated rats, while albumin therapy reduced infarct volume at these sites, on average, by 84% and 33%, respectively. Total infarct volume was reduced by 66% and brain swelling was virtually eliminated by albumin treatment. Microscopically, while infarcted regions of vehicle-treated rats had the typical changes of pannecrosis, infarcted zones of albumin-treated brains showed persistence of vascular endothelium and prominent microglial activation, suggesting that albumin therapy may help to preserve the neuropil within zones of residual infarction. CONCLUSIONS: These findings confirm the striking neuroprotective efficacy of albumin therapy in focal cerebral ischemia and reveal that this effect is associated with DWI normalization and a mitigation of pannecrotic changes within zones of residual injury.

The effect of high-dose albumin therapy on local cerebral perfusion after transient focal cerebral ischemia in rats.

We have shown that high-concentration albumin therapy is markedly neuroprotective in focal cerebral ischemia. The present study was conducted to ascertain the degree to which hemodynamic alterations are responsible for this therapeutic effect. Normothermic, physiologically regulated male Sprague-Dawley rats received a 2-h period of middle cerebral artery occlusion (MCAo) by insertion of an intraluminal suture coated with poly-L-lysine. Albumin (25% human serum albumin solution) or vehicle (0.9% sodium chloride) was administered intravenously at a dose of 1% of body weight immediately after suture withdrawal following 2-h MCAo. Local cerebral blood flow (LCBF) was measured autoradiographically with 14C-iodoantipyrine after 1 h of recirculation. Novel image-processing methods were used to compare average LCBF data sets against previously obtained infarction-frequency data on a pixel-by-pixel basis. Albumin therapy reduced mean hematocrit by 42% but produced no other systemic alterations. Pixel-based histopathological analysis revealed large, consistent cortical and subcortical infarcts in saline-treated rats with MCAo; albumin therapy reduced mean cortical infarct volume by 85%. Within regions showing albumin-associated neuroprotection, numbers of pixels having LCBF in the upper ischemic-core flow range (0.12-0.24 ml g-1 min-1) were reduced by 8.6-fold by albumin therapy when compared to saline-treated rats; and numbers of pixels with LCBF in the lower penumbral flow range (0.24-0.36 ml g-1 min-1) were reduced by 3. 1-fold in albumin-treated rats (p=0.04 by repeated-measures analysis of variance). Analysis of the [albumin-saline] 3-dimensional difference-image data set revealed a circumferential zone of statistically significant albumin-associated LCBF increase within the posterior portion of the ischemic hemisphere, surrounding the core-region of prior ischemia. Thus, high-concentration albumin therapy improves local perfusion to regions of critical LCBF reduction. The spatial extent of this LCBF effect, however, appears too small to account fully for the marked neuroprotective efficacy of this therapy. We suggest that other, non-hemodynamic mechanisms may also be contributory.

Pentoxifylline inhibits granulocyte and platelet function, including granulocyte priming by platelet activating factor.

Pentoxifylline has been claimed to work a beneficial effect in arterial insufficiency by improving erythrocyte deformability and thus improving blood flow. A number of observations, including the drug concentrations required to work the red cell effect, suggested that this was not likely to be a complete explanation. We therefore examined the effect of pentoxifylline on several granulocyte and platelet functions. Pentoxifylline inhibited platelet aggregation in response to 4 mumol/L adenosine diphosphate; although statistically significant inhibition was seen at 1 mumol/L pentoxifylline, over 200 mumol/L was required for 50% inhibition. The adherence of unstimulated platelets to cultured endothelial cells was not strongly inhibited by pentoxifylline; however, the additional increment in adherence seen in the presence of thrombin was strongly inhibited (50% attenuative dose [AD50] = 18 mumol/L). Granulocyte aggregation in response to C5a was modestly inhibited (AD30 approximately equal to 8 mumol/L; AD50 greater than 1 mmol/L), and the adherence of unstimulated polymorphonuclear neutrophils (PMNs) to endothelium was uninhibited. The C5a-mediated augmentation of PMN adherence to endothelium was mildly inhibited (AD50 = 240 mumol/L). Inhibition of PMN chemotaxis to N-Formyl-methionyl-leucyl-phenylalanine (FMLP) or C5a (AD50 = 12 mumol/L) and inhibition of superoxide production in response to FMLP-cytochalasin B (AD50 = 24 mumol/L) were seen at more clinically credible concentrations. Perhaps most important, pentoxifylline blocked the ability of platelet activation factor to prime neutrophils for enhanced response to subsequent stimuli (AD50 approximately equal to 8 mumol/L; AD60 = 10 mumol/L when production was the indicator system); in vivo, this could broaden the drug's effect to include functions that it does not inhibit potently in a primary fashion. Although pentoxifylline is known to be a phosphodiesterase inhibitor, and we found it to elevate intracellular cyclic adenosine monophosphate in stimulated PMNs, we found it to be only marginally more potent than theophylline in this regard; therefore, the failure of theophylline to inhibit PMN priming suggests that this enzyme inhibition is not a complete explanation of the pharmacologic action of pentoxifylline. We suggest that the effects of pentoxifylline on platelet and granulocyte function are likely to contribute to the drug's clinical efficacy.

Neutrophil oxidants inactivate alpha-1-protease inhibitor and promote PMN-mediated detachment of cultured endothelium. Protection by free methionine.

Activated granulocytes have been implicated in mediating pulmonary endothelial damage in the Adult Respiratory Distress Syndrome. In another lung disease, emphysema, pulmonary granulocytes (PMNs) are thought to be doubly responsible for lung dissolution: they release potent proteolytic enzymes including elastase, and they generate reactive oxygen species that oxidize a reactive site methionine group in alpha-1-protease inhibitor (alpha-1-PI) rendering it, in turn, impotent as an anti-elastase. This suggested an analogous scenario for pulmonary vascular damage: namely, undefended PMN elastase might also mediate endothelial injury. Our strategy to prove this notion used 51chromium-labeled human endothelial cells exposed to intact PMN or to enucleate "neutroplasts." The latter are elastase-free cytoplasmic blebs derived from PMN. When activated, both PMN and neutroplasts generate similar amounts of toxic oxygen species; yet neutroplasts caused insignificant endothelial damage, measured as 51Cr "lift-off"from anchoring matrix (PMN = 24.3% +/- 1.8% vs neutroplast = 1.2% +/- 0.4%; p less than 0.001). Adding pure elastase back to neutroplasts increased endothelial cell lift-off (7% +/- 0.2%). Although the prototypic serine protease inhibitor phenyl methylsulfonylfluoride (PMSF) protected endothelium from PMNs, pure alpha-1-PI (also a potent anti-elastase) when added in physiologic amounts did not protect endothelial cells from PMN assault, suggesting that PMN oxidants might inactivate it. By adding exogenous myeloperoxidase (MPO) to MPO-deficient neutroplasts, we demonstrated that MPO-dependent oxidants, probably N-chloramines, are critical inactivators of alpha-1-PI. This was further confirmed since added free methionine, a scavenger of chloramine, protected alpha-1-PI from inactivation by reagent chloramine or that produced by rearmed neutroplasts or PMN.(ABSTRACT TRUNCATED AT 250 WORDS)