Acute alterations in microvascular basal lamina after subarachnoid hemorrhage

OBJECT: Aneurysmal subarachnoid hemorrhage (SAH) causes acute and delayed ischemic brain injuries. The mechanisms of acute ischemic injury following SAH are poorly understood, although an acute increase in microvascular permeability has been noted. The integrity of cerebral microvessels is maintained in part by components of basal lamina: collagen IV, elastin, lamina, and so forth. Destruction of basal lamina components by collagenases and matrix metalloproteinases (MMPs), especially MMP-9, has been known to occur in other ischemic models. The authors assessed the integrity of cerebral microvasculature after acute SAH by examining collagen IV and MMP-9 levels and collagenase activity in the microvessels. METHODS: Subarachnoid hemorrhage was induced in rats through endovascular perforation of the intracranial bifurcation of the internal carotid artery. Animals were killed 10 minutes to 48 hours after SAH or sham operation (time-matched controls). Levels of collagen IV and MMP-9 were studied in the microvasculature by performing immunoperoxidase and immunofluorescence staining, and collagenase activity was assessed by in situ zymography. Little change occurred in collagen IV and MMP-9 immunostaining or collagenase activity at 10 minutes or 1 hour after SAH. Starting 3 hours after SAH, collagen IV immunostaining was reduced or eliminated along segments of microvessels whereas MMP-9 staining was segmentally increased. These effects reached a maximum at 6 hours and returned toward those values in sham-operated controls at 48 hours. CONCLUSIONS: Results of this study demonstrated an acute loss of collagen IV from the cerebral microvasculature after SAH and indicated that MMP-9 contributes to this event. The loss of collagen IV might contribute to the known failure of the blood-brain barrier after SAH.     

Reversal of Cerebral Vasospasm by the Nitric Oxide Donor SNAP in an Experimental Model of Subarachnoid Haemorrhage

The constant release of nitric oxide (NO) is essential to maintain basal cerebrovascular tone. Oxyhaemoglobin, liberated by lysis of red blood cells after subarachnoid haemorrhage binds NO and prevents its entry into vascular smooth muscle cells. While endothelium-dependent vasoconstriction is preserved, decreased levels of NO inhibit endothelium-dependent relaxation and may cause vasospasm. S-nitrosothiols are potent vasodilators and precursors of NO. The authors' aim was to determine whether S-nitroso-N-acetylpenicillamine (SNAP), a stable S-nitrosothiol compound, could reverse vasospasm in an experimental vasospasm model in rabbit. Experimental subarachnoid haemorrhage (SAH) was induced in 37 New Zealand white rabbits. The animals were divided into four groups. Control (no SAH), SAH only, SAH plus saline and SAH plus SNAP. SNAP (15 micrograms/kg/min) or 0.09% saline (equal volume) was infused 46 hours after induction of SAH. All animals were killed by perfusion fixation 48 hours after SAH occurred. Basilar arteries were removed, sectioned and their cross sectional areas were evaluated in a blind manner, by light microscopy and by using computer assisted morphometry. Experimental SAH elicited vasospasm in all animals of SAH only and SAH plus saline group. In animals treated with SNAP, arterial narrowing was markedly attenuated without producing systemic hypotension. This widening achieved statistical significance when compared to the arteries of the SAH only and SAH plus saline group (p < 0.01). This study indicates that the NO donor SNAP is a potentially useful drug to reverse cerebral vasospasm due to SAH.     

Inducible nitric oxide synthase: a possible key factor in the pathogenesis of chronic vasospasm after experimental subarachnoid hemorrhage.

OBJECT: The role of nitric oxide (NO) in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH) is not well understood. Nitric oxide is a well-established vasodilatory substance; however, in SAH, NO may become a major source for the production of injurious free-radical species, leading to chronic cerebral vasospasm. Reactive overproduction of NO to counteract vascular narrowing might potentiate the detrimental effects of NO. The focus of the present study is to determine the extent of reactive induction of inducible nitric oxide synthase (iNOS) after experimental SAH. METHODS: Chronic vasospasm was induced in male Wistar rats by an injection of autologous blood (100 microl) into the cisterna magna followed by a second injection 24 hours later. A control group of 10 animals was treated with injections of 0.9% sodium chloride solution. Vasospasm was verified by pressure-controlled angiography after retrograde cannulation of the external carotid artery 7 days later. In 11 of 15 animals radiographic evidence of cerebral vasospasm was seen. The animals were perfusion fixed and their brains were removed for immunohistochemical assessment. With the aid of a microscope, staining for iNOS was quantified in 40-microm floating coronal sections. Immunohistochemical staining for iNOS was markedly more intense in animals with significant angiographic evidence of vasospasm. Virtually no staining was observed in control animals. Seven days after the second experimental SAH, labeling of iNOS was found in endothelial cells, in vascular smooth-muscle cells, and, above all, in adventitial cells. Some immunohistochemical staining of iNOS was observed in rod cells (activated microglia), in glial networks, and in neurons. CONCLUSIONS: The present study demonstrates induction of iNOS after experimental SAH.     

Evaluation of the microvasculature and cerebral ischemia after experimental subarachnoid hemorrhage in dogs

OBJECT: Whether cerebral vasospasm occurs only in surface vessels or also in parenchymal arterioles is debatable. The present study was undertaken to evaluate comprehensively the microvasculature of the brainstem after experimental subarachnoid hemorrhage (SAH). METHODS: Nine mongrel dogs of either sex, each weighing between 18 and 24 kg, underwent double blood injections spaced 48 hours apart; the injections were infused into the cisterna magna immediately after angiography of the basilar arteries (BAs). Three additional dogs assigned to a control group received no blood injections. The dogs were killed on Day 7. Axial sections obtained from the midpontine region of both control dogs and animals subjected to SAH were evaluated with respect to the morphological characteristics of vessels and neurons, and for ultrastructural changes. Severe vasospasm occurred in the BAs of all dogs subjected to SAH. Nevertheless, in these animals, the luminal areas and vessel perimeter in parenchymal arterioles, but not in parenchymal venules, were observed to have increased when compared with those of control dogs (p < 0.01, t-test). No corrugation of the internal elastic lamina was observed and smooth-muscle and endothelial cells remained normal at the ultrastructural level in the dogs with SAH. CONCLUSIONS: In this model, vasospasm of the BAs did not extend into the region of the pons to affect the intraparenchymal arterioles. Dilation of the parenchymal arterioles might serve as compensation for reduced blood flow. Thus, no neuronal ischemia or infarction resulted in the pontine region of the brain.     

Nitrosoglutathione triggers collagen deposition in cutaneous wound repair

The presence of nitric oxide (NO) is associated with enhanced wound fibroblast collagen synthesis; previous observations have focused on the effect of NO on wound collagen content. This article emphasizes the effect of nitrosothiols on wound collagen deposition and matrix-metalloproteinase activity, which is the primary breakdown pathway of collagen. We examined the effects of S-nitrosoglutathione (GSNO) and glutathione (GSH) on rat scar tissue. Hydroxyproline content, matrix metalloproteinase activity, total glutathione, and total nitrite of scar tissue were measured 3, 5, 7, and 10 days after wounding. It was observed that, at Day 5 and Day 10, wound collagen content was 52.0 percent and 47.5 percent higher, respectively, after GSNO administration than in controls (p<0.05). GSH administration decreased wound collagen deposition 76.5 percent by Day 5 (p<0.05). GSH lowered the matrix metalloproteinase activity 67 percent at Day 5 and 50 percent (p<0.05) at Day 10. Nitrite and nitrate levels were 55 percent higher in the GSNO treated rats than in the control group (p<0.05) at Day 3, whereas the GSH-treated groups showed no changes. GSNO increased systemic nitrite 53 percent 3 hours after intraperitoneal injection. Our findings suggest that collagen deposition increases in cutaneous wound healing after the administration of GSNO and that this nitrosothiol does not interfere with the collagenolytic pathway, thus maintaining the physiological conditions necessary for wound healing.     

Therapeutic effects of intracarotid infusion of spermine/nitric oxide complex on cerebral vasospasm

BACKGROUND: Vasospasm is one of the underlying causes of morbidity and mortality in subarachnoid haemorrhage (SAH). The therapeutic effects of intracarotid infusion of spermine/nitric oxide complex (SPER/NO) on cerebral vasospasm in an experimental model of SAH were investigated. METHOD: Twenty-four adult male New Zealand white rabbits (2.6-3.4 kg in weight) were randomly divided into four groups (n=6), as follows: (I) control group (without SAH and drug), (II) SAH alone group (with SAH, without drug), (III) SAH placebo group (with SAH and saline), and (IV) SAH-SPER/NO group (with SAH and SPER/NO). The fresh autologous non-heparinized blood was injected into the cisterna magna to induce a SAH, after 24 hour SAH, the substance (saline or SPER/NO) was delivered to animals. All rabbits were scarified at 48-hours of induced SAH. The basilar artery with surrounding tissue was removed from the cranium and processed for paraffin embedding. Histopathological and stereological examinations of the basilar artery were done. FINDINGS: In the SPER/NO treated group of rabbits, the histopathological changes were less severe than in the SAH-alone and SAH-placebo groups. Regarding the intracarotid pressure, there was a statistically significant difference between SAH-alone and SAH-SPER/NO groups and also between SAH-SPER/NO and control groups (p<0.05). The mean cross sectional area of basilar arteries was 0.26 mm(2) in the control, whereas in SAH alone, placebo and SAH-SPER/NO groups were 0.13, 0.15 and 0.20 mm(2), respectively. INTERPRETATION: It is well known that NO is a critical substance involved in cerebral vascular dynamics. Present results indicate that treatment of vasospasm with SPER/NO in SAH may be promising. However, further studies should be done on this substance to clarify its effect on vasospasm before using the drug in clinical situations.     

Pharmacological reversibility of experimental cerebral vasospasm

Using a morphometric technique, the pharmacological reversibility of luminal narrowing after experimental subarachnoid hemorrhage (SAH) was investigated. For vasodilation, a "cocktail" consisting of 10(-4) M papaverine, 2 x 10(-4) M sodium nitroprusside, and 10(-5) M adenosine was administered intra-arterially. Forty-two rabbits were divided into six groups: control (normal animals); control plus cocktail (normal animals perfused with the cocktail before fixation); SAH (animals sacrificed 48 hours subsequent to intracisternal injection of 1.5 ml/kg of arterial blood); SAH plus cocktail (SAH plus perfusion with the cocktail); BaCl2 (animals sacrificed 10 minutes after intracisternal injection of 2 ml of 3 x 10(-3) M BaCl2); and BaCl2 plus cocktail (BaCl2 animals perfused with the cocktail). The diameter of the basilar arteries in the control and the control plus cocktail groups was not significantly different. BaCl2 reduced the diameter 44% and SAH reduced the diameter 27%. There were no significant differences between the diameter of the BaCl2 plus cocktail group and SAH plus cocktail group when compared with the control or the control plus cocktail group. Morphological examination by light and transmission electron microscopy showed luminal narrowing and corrugation of the elastic lamina with few degenerative or proliferative changes of the vessel wall in animals with SAH. These results suggest that cerebral vasospasm is caused initially by smooth muscle contraction rather than by proliferative vasculopathy and that it is not an irreversible process.     

Acute microvascular platelet aggregation after subarachnoid hemorrhage

OBJECT: The mechanisms underlying acute cerebral ischemia after subarachnoid hemorrhage (SAH) are not well established. Platelets aggregate within major cerebral vessels hours after SAH, but this has not been studied in the microvasculature. Platelet aggregates within the microvasculature could mechanically obstruct the lumen and initiate events that injure vessel structure. In the present study the authors examined the hypothesis that platelets aggregate within the cerebral microvasculature acutely after SAH. METHODS: Subarachnoid hemorrhage was induced in the rat by using the endovascular perforation model. The animals were killed between 10 minutes and 48 hours after SAH. Immunostaining for the platelet surface receptor glycoprotein (GP)IIb/IIIa, which mediates platelet aggregation, was used to detect platelet aggregation. Sham-operated animals were used as controls. The GPIIb/IIIa immunoreactive platelet aggregates were abundant in the microvasculature of the basal and frontal cortex, striatum, and hippocampus 10 minutes after SAH. These aggregates decreased in number from 1 to 6 hours post-SAH and then increased to a peak at 24 hours. No immunoreactive aggregates were observed 48 hours after SAH. CONCLUSIONS: The data indicate that widespread platelet aggregation occurs very rapidly in response to SAH followed by a decrease within 6 hours and a subsequent increase 24 hours after SAH. Microvascular platelet aggregates may contribute to decreased cerebral blood flow and ischemic injury after SAH via a number of mechanisms.     

Type IV collagen,type IV collagenase activity and ability of cell proliferation in human thyroid tumours

BACKGROUND: The processes of malignant tumour invasion and metastasis are known to include the destruction of cell stroma and vascular basement membrane. It has been suggested that type IV collagenase degrades type IV collagen, a main component of the basement membrane. METHODS: In our study, type IV collagenase activity in human thyroid tumours was measured by the Liotta method. The degree of destruction of diseased regions of thyroid tumours was immunohistochemically determined by anti-type IV collagen antibody staining. Cell proliferation in the tumours was estimated using anti-proliferating cell nuclear antigen (PCNA) and epidermal growth factor receptor (EGFR). RESULTS: T4 thyroid carcinomas with higher type IV collagenase activity and very weak type IV discontinuous immunostaining for type IV collagen of follicular basement membranes, exhibited many PCNA or EGFR positive cells. In benign tumours, normofollicular- or macrofollicular-type tumours with low type IV collagenase activity showed few PCNA and EGFR positive cells and intact type IV collagen of basement membranes, as seen in normal thyroids. Conversely, an atypical adenoma with higher type IV collagenase activity showed many PCNA and EGFR positive cells and weak type IV discontinuous immunostaining for type IV collagen, as in thyroid carcinomas. CONCLUSION: These findings suggest that staining for type IV collagen and type IV collagenase activity reflect the ability of cell proliferation, and help predict the aggressiveness of invasion and metastasis in human thyroid tumours.     

Symptomatic arterial luminal narrowing presenting months after subarachnoid hemorrhage and aneurysm clipping

The authors describe three cases of clinical cerebral ischemia associated with angiographic evidence of cerebral arterial luminal narrowing presenting 7, 14, and 52 weeks after subarachnoid hemorrhage (SAH) and aneurysm clipping. Delayed vasospasm, in its usual time setting 1 or 2 weeks after hemorrhage, did not occur symptomatically in these patients. No evidence for aneurysm clip migration or rebleed was present. All patients responded favorably to volume expansion and elevation of blood pressure. This unusual occurrence of a very delayed vasospasm may further the understanding of the vasospastic process. The symptomatic onset of arterial luminal narrowing months after SAH may suggest that a proliferative vasculopathy more accurately explains the observed vessel narrowing, rather than conventional active constriction of vascular smooth muscle.     

Dexamethasone preventing contractile and cytoskeletal protein changes in the rabbit basilar artery after subarachnoid hemorrhage

OBJECT: The aim of this project was to study the perturbations of four smooth-muscle proteins and an extracellular protein, type I collagen, after subarachnoid hemorrhage (SAH) and to examine the possible preventive effects of dexamethasone. METHODS: Using a one-hemorrhage rabbit model, the authors first examined the effects of SAH on the expression of alpha-actin, h-caldesmon, vimentin, smoothelin-B, and type I collagen; second, they studied whether post-SAH systemic administration of dexamethasone (three daily injections) corrected the induced alterations. Measurements were obtained at Day 7 post-SAH. The proteins were studied by performing immunohistochemical staining and using a laser-scanning confocal microscope. Compared with control (sham-injured) arteries, the density of the media of arteries subjected to SAH was reduced for alpha-actin (-11%, p = 0.01) and h-caldesmon (-15%, p = 0.06) but increased for vimentin (+15%, p = 0.04) and smoothelin-B (+53%, p = 0.04). Among animals in which SAH was induced, arteries in those treated with dexamethasone demonstrated higher values of density for alpha-actin (+13%, p = 0.05) and h-caldesmon (+20%, p = 0.01), lower values for vimentin (-55%, p = 0.05), and nonsignificantly different values for smoothelin-B. The density of type I collagen in the adventitia decreased significantly after SAH (-45%, p = 0.01), but dexamethasone treatment had no effect on this decrease. CONCLUSIONS: The SAH-induced alterations in the density of three of four smooth-muscle proteins were prevented by dexamethasone treatment; two of these proteins--alpha-actin and h-caldesmon--are directly related to contraction. This drug may potentially be useful to prevent certain morphological and functional changes in cerebral arteries after SAH.     

Appearance of collagen fibers in the cerebral vascular wall following subarachnoid hemorrhage.

Ultrastructural examinations of the cerebral vascular wall following subarachnoid hemorrhage (SAH) demonstrated that collagen fibrils developed in the muscle layer near the adventitia in the early stage of SAH and increased in number and volume with time. These findings suggest that accelerating factors of collagen synthesis in the muscle layer may be released from the adventitial side, and collagen synthesis is induced by extravascular factors. The changes of collagen volume with time suggest collagen to be an important phenomenon of persistent vasospasm after SAH. Histoimmunological studies showed that increased collagen fibers in the tunica media were mainly type III collagen, implying that cerebral vasospasm may be related to chemical inflammation.     

Nitric oxide synthase in acute alteration of nitric oxide levels after subarachnoid hemorrhage

OBJECTIVE: Subarachnoid hemorrhage (SAH) is associated with acute decreases and subsequent recovery of cerebral nitric oxide (NO) levels, but the mechanisms of these alterations are not known. In this study, we measured NO synthase (NOS) protein and kinetics to determine its involvement in the alterations of cerebral NO levels after SAH. METHODS: The endovascular rat model of SAH was used. The number of NOS-1 (neuronal) and NOS-2 (inducible)-positive cells (0-96 h) was determined by counting immunoreactive cells in 8-microm cryostat sections. The tissue content of active NOS and its kinetic parameters were studied with an enzymatic l-citrulline assay. RESULTS: The number of NOS-1-positive cells increased between 1 and 3 hours after SAH, decreased to and below control values at 6 and 72 hours after SAH, and increased to control values 96 hours after SAH. The number of NOS-2-positive cells increased 1 hour after SAH, decreased to control values at 24 hours, and increased above control values 96 hours after SAH. The Michaelis-Menten kinetic parameters (V(max), K(m), slope) of NOS remained unchanged at 10 and 90 minutes after SAH. CONCLUSION: NOS-1 and -2 proteins undergo a triphasic alteration after SAH, whereas the amount of active NOS and its kinetic parameters remain unchanged during the first 90 minutes after SAH. Depletion of NOS is not involved in the acute alterations of cerebral NO levels after SAH.     

Effect of combined antisense oligonucleotides against high-glucose- and diabetes-induced overexpression of extracellular matrix components and increased vascular permeability

The effect of combined antisense oligonucleotides (AS-oligos) against overexpression of extracellular matrix (ECM) components, fibronectin, laminin, and collagen IV and on cell monolayer permeability was examined in rat microvascular endothelial cells (RMECs) grown in high glucose medium and on retinal vascular permeability in diabetic rats. RMECs grown in high glucose for 10 days and transfected with combined AS-oligos showed a significantly reduced fibronectin, laminin, and collagen IV protein level. In parallel studies, high-glucose-induced excess monolayer permeability was also reduced in RMECs transfected with the combined AS-oligos. Similarly, diabetic rats intravitreally injected with the combined AS-oligos and examined after 2 months of diabetes showed significant reduction in retinal fibronectin, laminin, and collagen IV expression. In addition, vascular permeability, as determined from extravasation of fluorescein isothiocyanate-BSA in the surrounding areas of the retinal capillaries, was partially reduced in the combined AS-oligos-treated diabetic retinas. Our results indicate that the combined AS-oligos strategy is effective in simultaneously reducing fibronectin, collagen IV, and laminin overexpression and reducing vascular leakage in the retinal capillaries of diabetic rat retinas. The findings suggest that abnormal synthesis of ECM components may contribute to vascular leakage in the diabetic retina.     

Involvement of vasopressin in brain edema formation: further evidence obtained from the Brattleboro diabetes insipidus rat with experimental subarachnoid hemorrhage

Brain water accumulation (1.2%) with an accompanying increase in the sodium content was observed in Wistar rats as early as 1 hour after experimental subarachnoid hemorrhage (SAH). After 6 and 24 hours, the water content was 1.3 and 1.4%, respectively, higher than that of control animals. In contrast, in Brattleboro diabetes insipidus rats the content of brain water and electrolytes had not changed significantly 1 hour after the administration of blood into the subarachnoid space. Increased brain water and sodium and a normal potassium content, indicative of a vasogenic type of brain edema, were seen at 6 hours after SAH. In these animals, known to be devoid of vasopressin, the increase in brain water 24 hours after SAH was 2.6%, compared with 1.4% for Wistar rats with SAH. It is suggested that the lack of vasopressin could alter the course of brain edema formation after experimental SAH in Brattleboro diabetes insipidus rats. It is hypothesized that vasopressin, by regulating the water permeability of the brain capillaries, the choroid plexus, and the cerebrospinal fluid absorption structures, plays an important role in controlling the brain fluid and electrolyte balance during the course of SAH.     

Spontaneous rupture of hepatocellular carcinoma and vascular injury

HYPOTHESIS: Because spontaneous rupture of hepatocellular carcinoma (HCC) is one kind of bleeding complication related to the blood vessels, the possible mechanism of this rupture should occur on the blood vessel itself. Our hypothesis, which has not yet been investigated, is that the vascular integrity of HCC might be damaged during vascular injury. DESIGN: We examined semiquantitatively the expression of von Willebrand factor, elastin, neutrophil elastase, type IV collagen, and collagenase in 23 specimens of HCC with spontaneous rupture by immunohistochemistry, and compared them with 30 specimens of HCC without rupture. RESULTS: There was a significant decrease of von Willebrand factor, proliferation of degenerated elastin, abnormal distribution of neutrophil elastase, degradation of type IV collagen, and increase in collagenase production around the blood vessels in ruptured HCC. Since the decreased expression of von Willebrand factor is an indicator of vascular injury and elastase and collagenase are present in inflammatory processes, we postulate that the vascular injury probably exists before spontaneous rupture of HCC occurs. The blood vessel dysfunction resulting from the degeneration of elastin and the degradation of type IV collagen can render the blood vessels stiff and weak, causing them to split easily when the vascular load increases from hypertension or minor mechanical trauma. CONCLUSION: Spontaneous rupture of HCC may be related to the vascular dysfunction.     

The effect of nicardipine on vasospasm in rabbit basilar artery after subarachnoid hemorrhage

This study was performed to examine the effect of the dihydropyridine calcium antagonist, nicardipine, on vasospasm after experimental subarachnoid hemorrhage (SAH) in the rabbit. The study was carried out in two parts: 1) effect of intravenous nicardipine (n = 45) and 2) effect of intracisternal nicardipine (n = 21). SAH was induced by injecting 5 ml of autologous arterial blood into the cisterna magna. In the intravenous study, there were five groups: 1) SAH without treatment; 2) SAH with vehicle (saline); 3) SAH and intravenous infusion of low-dose nicardipine (0.01 mg/kg/h); 4) SAH and intravenous infusion of high-dose nicardipine (0.15 mg/kg/h); and 5) controls without SAH. The intravenous infusions were started immediately after SAH and continued for 48 hours until death. In the intracisternal study, there were three groups: 1) SAH without treatment; 2) SAH with intracisternal administration of nicardipine (0.37 mg/h); and 3) controls without SAH. Intracisternal infusions were begun 70 hours after SAH and continued for 2 hours until death. After perfusion-fixation, the basilar artery was removed and processed for morphometric analysis. In the intravenous study, vessels from animals subjected to SAH were significantly narrowed when compared with controls, although after high-dose nicardipine vessel caliber was slightly larger than in the other SAH groups. Animals given intracisternal nicardipine showed a nonsignificant reduction of caliber as compared with controls: only 12% decrease in diameter and 22% decrease in luminal area. In the rabbit SAH model, nicardipine had a very modest effect on vasospasm at the doses tested.     

New direct assay method of type IV collagenase in tissue homogenate and biochemical role of collagenase against type I, and IV collagens to the invasion of the stomach and lung cancer

In order to study the role of both collagenases against type I and type IV collagen (type I and type IV collagenase) with regard to tumor invasion and metastasis, the activities of both collagenases in tissue homogenate in each 40 cases of stomach and lung cancers were investigated. The direct assay method of type IV collagenase in tissue was established through modification of Liotta's method. In stomach cancer, the part of advancing front of cancer showed the highest activity of type I collagenase. The adjacent mucosa to cancer also showed high activity of type IV collagenase. The cancer tissues that had the remarkable finding of vascular invasion of cancer cells showed high activity of type IV collagenase. In lung cancer, the correlation between the size of cancer mass and activity of type I collagenase was shown. Squamous cell carcinoma in comparison to adenocarcinoma had higher activity of type I collagenase and poor activity of type IV collagenase. These results suggested that the activity of type I collagenase might participate in local invasion and the activity of type IV collagenase might be associated with vascular invasion of cancer through disruption of basement membrane and they could be one of the useful biochemical tumor marker to represent the growth and metastatic pattern.     

The novel 5-lipoxygenase inhibitor ABT-761 attenuates cerebral vasospasm in a rabbit model of subarachnoid hemorrhage

OBJECTIVE: Eicosanoids have been implicated in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). Leukotrienes, 5-hydroxyperoxyeicosatetraenoic acid, and 5-hydroxyeicosatetraenoic acid are part of this group of substances, resulting from the 5-lipoxygenase activity on arachidonic acid metabolism. This study examined the effects of ABT-761, a new 5-lipoxygenase inhibitor, on cerebral vasospasm in an in vivo rabbit model of SAH. METHODS: A total of 48 rabbits were assigned to one of six groups: SAH + placebo (n = 8), SAH + ABT-761 20 mg/kg (n = 8), SAH + ABT-761 30 mg/kg (n = 8), control + placebo (n = 8), control + ABT-761 20 mg/kg (n = 8), and control + ABT-761 30 mg/kg (n = 8). Drug administration was initiated 30 minutes after induction of SAH and repeated 24 hours later. The animals were killed 48 hours after SAH, using the perfusion-fixation method. The cross sectional areas of basilar artery histological sections were measured by an investigator blinded to the treatment groups of the individual samples. RESULTS: In placebo-treated animals, the average luminal cross sectional area of the basilar artery was reduced by 68% after SAH as compared with controls (P < 0.0001). After SAH, the vasospastic response was attenuated in animals treated with 20 or 30 mg/kg representing a 28 or 35% reduction, respectively (P = 0.0011 and P = 0.0038). CONCLUSION: The results demonstrated that ABT-761 is effective in attenuating experimental cerebral vasospasm, indicating that this new drug represents a potential therapeutic agent for the treatment of vasospasm after SAH.