Figure 5 - uploaded by Masa-aki Oikawa
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Transparent specimen of the blood vessels distributed in the mesentery of Figs 2 and 3. The small artery had a moniliform morphology; that is, segments that were either contracted or dilated were observed frequently. (a) Small artery that appears to be in arteriospasm. (b) Small vein. Low power magnification.
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To evaluate the effects of endotoxin on the morphology of the equine mesenteric vasculature, each of two thoroughbred horses were given two intravenous injections (24 h apart) of a sublethal dose of endotoxin (10 microg/kg). Each injection produced results similar to those of clinical cases of equine colic with obstructive nature of the loop of bow...
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Context 1
... dehydrated with alcohol, and soaked in methyl salicylate to prepare transparent specimens. On observation of specimens with transmission light to examine the morphology of the blood vessels distributed in the mesentery, many small arteries appeared moniliform; that is, there were many small arteries that were contracted or dilated in segments (Fig. 5). The small veins were also dilated. On examination of serial sections of the small arteries the contracted segments had oedematous and loosened walls and partial parietal hyalinization. The lumina were very M. OIKAWA and J. SHIGA narrow (Fig. 3). In the dilated segments there were intramural and extramural haemorrhages in all layers of ...
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... Although a specific cause for the lesions has not been yet iden fied, the similarity in the clinical histories and consistency in the pathological findings in all 4 cases suggest a possible common e ology leading to increased vascular permeability concurrently in mul ple mesenteric vessels. Bacterial endotoxemia (lipopolysaccharide) has been associated with similar but milder pathological findings in horses in both spontaneous and experimental 1,2,[5][6][7]9 cases, although the clinical picture of endotoxemia in horses is not typically characterized by hemoperitoneum and sudden death. We were unable to assess endotoxemia in these cases because of the lack of premortem blood needed for the analysis. ...
... [20][21][22] At the vascular level, LPS may induce endothelial dysfunction 19,23 or vascular damage. 24,25 Arachidonic acid products alter EDV responses after LPS exposure, 18,26 although the role played by COX-2 and the mechanism underlying its action have not yet been specified. Lipopolysaccharide via the reduced form of NADPH oxidase 27 or COX-2 28 may act as a source of ROS. ...
To investigate the role of superoxide anions in the lipopolysaccharide (LPS)-induced impairment of beta-adrenoceptor-mediated equine digital vein (EDV) vasodilation.
EDVs isolated from forelimbs of 24 healthy adult horses.
Endothelium-intact or endothelium-denuded EDV rings were incubated with or without LPS (10 microg/mL) of Escherichia coli (O55:B5) for 4 hours. Cumulative concentration-relaxation curves resulting from administration of isoprenaline, a nonselective beta-adrenoceptor agonist, or from administration of SR 58611A, a selective beta(3)-adrenoceptor agonist, were recorded in phenylephrine-preconstricted EDVs in the absence or the presence of superoxide dismutase (200 U/mL). Isoprenaline-induced relaxation was also evaluated with or without the cyclooxygenase inhibitors indomethacin (10 microM) and NS-398 (10 microM).
Isoprenaline and SR 58611A induced concentration-dependent relaxation of EDV rings, which was inhibited by LPS exposure. Superoxide dismutase abolished the inhibitory effect of LPS on the isoprenaline- and SR 58611A-mediated relaxation. Pretreatment of the LPS-treated EDVs with indomethacin or NS-398 restored the isoprenaline-mediated relaxation and abolished the LPS-induced impairment to a similar extent as superoxide dismutase.
Results supported a role of superoxide anions in the LPS-induced impairment of beta-adrenoceptor-mediated EDV vasodilation. The LPS-induced oxidative stress in EDVs may contribute to vascular dysfunctions associated with laminitis in horses.
... 12 Several investigators reported the use of PTAH stain to identify fibrin deposits in laboratory animals with DIC with satisfactory results. [13][14][15][16][17] In horses, the efficacy of PTAH to detect fibrin deposits was proposed by some investigators [18][19][20] and was demonstrated in the previous study in which 40% of the horses with severe gastrointestinal disorders revealed fibrin deposits in their tissues. 1 However, even with special stains, incompletely polymerized fibrin is difficult to demonstrate, 21 and misdiagnosis may occur. ...
Histochemical and immunohistochemical techniques have been used to detect fibrin deposits in different tissues in humans and experimental animal models with disseminated intravascular coagulation (DIC). Fibrin deposits also have been observed in horses with severe ischemic and inflammatory disorders by histochemical stainings (phosphotungstic acid hematoxylin [PTAH]).
Immunohistochemical (IHC) methods can be used to accurately detect fibrin deposits in horses at risk of DIC.
Tissue-organ samples collected on postmortem examination from 87 horses with severe inflammatory and ischemic gastrointestinal disorders. In addition, tissue samples from 13 horses with colic and colonic obstructions or displacements and from 13 slaughter horses were used as controls.
Tissue samples (kidney, lung, and liver) were stained with PTAH and IHC for blinded histologic examination and comparison. A fibrin score (grades 0 to 4) was established for each tissue sample and for each horse for both techniques.
When the IHC method was used, fibrin deposition was observed in 47.1% of the horses with colic with a poor prognosis, compared with 41.4% with PTAH. An agreement of 70% was achieved when both methods were compared, and the lung was confirmed as the most affected organ. Almost none of the colic and slaughter control horses had fibrin deposits in their tissues.
IHC technique for fibrin antigens was very effective in the detection and identification of fibrin deposits in equine tissues and may be a reliable technique for the postmortem diagnosis of DIC.
... There is a growing body of evidence to suggest that endotoxins play an important role in the pathogenesis of a number of colics (Moore and Barton, 2003). Previously, we reported that mesenteric arterionecrosis (MA), in which the arterial lesions were characterized by medial necrosis accompanied by intramural and transmural haemorrhage (erythrodiapedesis) and the deposition of fibrinoid substances within the media of the mesentery, in two Thoroughbred horses with experimentally induced endotoxaemia (ET) (Oikawa and Shiga, 2002) was closely similar to that seen in a Thoroughbred horse with naturally occurring ET associated with spontaneous colic (Oikawa et al., 2004). The luminal diameter of affected arteries ranged from approximately 50 to 300 mm (arteriole to small artery). ...
... We hypothesized that MA occurs in most cases of naturally occurring equine endotoxaemia with colic. To test this hypothesis, the present study was designed to compare the morphology of the mesenteric vasculature in 15 Thoroughbred horses with spontaneous colic suspected to be due to ET with that of six Thoroughbred horses with experimentally induced ET, including two horses (nos 5 and 6) that had been studied previously (Oikawa and Shiga, 2002;Oikawa and Yamaoka, 2003). ...
... The LPS was given as an abrupt bolus infusion (i.e., an intravenous injection lasting no more than 20 sec of a dose high enough to obtain noticeable effects) at 10 mg/kg to two horses (Group A; 1 and 2) and at 20 mg/kg to two other horses (Group B; 3 and 4). Two horses (Group C; 5 and 6) used in our previous studies (Oikawa and Shiga, 2002;Oikawa and Yamaoka, 2003) had also received an abrupt bolus infusion (10 mg/kg on two occasions 24 h apart). Two control horses (7 and 8) were given an injection of 20 ml of pyrogen-free sterile isotonic saline into the left jugular vein on two occasions 24 h apart. ...
To test the hypothesis that mesenteric arterionecrosis (MA) occurs in horses with naturally occurring endotoxaemia (ET) and in those with experimentally induced ET, the mesentery and gastrointestinal tract of 21 Thoroughbred racehorses (15 with spontaneous colic suspected to be due to ET, and six with experimentally induced ET) were examined. MA, which occurred in 13 of the 15 horses with spontaneous colic and in all six of the cases of experimental ET, was morphologically similar in the two groups of animals. This suggested that the pathogenesis of the MA was fundamentally similar in the two groups, and that MA is a pathognomonic feature of equine ET. In addition to histolysis of the arterial walls associated with infiltration of blood components, changes were noted in the medial smooth muscle including formation of many intracellular vacuoles within single smooth muscle cells, cytoplasmolysis, necrosis with granules and vacuoles, and coagulation necrosis; similar changes have been observed in cases of prolonged angiospasm or vasoconstriction. It is suggested that the effects of sustained arterial contraction leading to intimal and medial damage influence the pathomorphogenesis of MA.
... However, we cannot rule out ultrastructural changes happening at the endothelial cell level. Higher endotoxin doses (10 lg/kg) have been reported to induce histopathological changes in mesenteric arteries, 24 h post-administration (Oikawa and Shiga, 2002). It is possible that allowing a longer exposure time to the low endotoxin dose used here, could induce observable endothelial changes. ...
Endotoxaemia is a syndrome linked to the development of equine laminitis; however, the relationship between them is uncertain. The aim of this experiment was to evaluate the effect of an experimental acute sublethal endotoxaemia model on in vitro equine palmar digital vascular reactivity. Rings of arteries and veins of each forelimb were obtained from 11 clinically healthy horses submitted to two surgical procedures, 3 weeks apart. Before the second surgery, 0.25 microg/kg of lipopolysaccharide from Escherichia coli O55:B5 in saline, was administered i.v. in 30 min. After 3 h, the vessels were harvested and submitted to in vitro vascular reactivity experiments and histopathology. The response to depolarizing Krebs solution (DKS, 40 mm), phenylephrine (PHE), acetylcholine (ACh) and sodium nitroprusside (SNP) were evaluated. All horses showed colic pain and watery diarrhoea, tachycardia, tachypnea, hyperthermia and leucopenia. Concentration-response curve (CRC) to PHE was shifted to the left in arteries rings from endotoxemic horses without any effect on vein rings. The CRC to ACh was shifted to the right with a reduction in the maximal response. The response to SNP and DKS was similar between groups. There was no evidence of histopathological effects. The increased response to PHE in digital arteries together with a reduction of the endothelium-dependent response to ACh in arteries and veins, confirm the existing reports where endotoxaemia was found to modify the digital vascular reactivity during the acute phase. As the digital endothelial function is impaired, there may be an increased potential to develop a digital prothrombotic state with a reduced vasodilatory capacity.
... Equine endotoxaemia occurs in at least 25 % of horses admitted with colic (King and Gerring, 1988). An experimental study by Oikawa and Shiga (2002) suggested that endotoxin-induced damage to the equine mesenteric arteries resulted in a disturbance of intestinal blood flow and motility. The mesenteric circulation system has one of the body's largest vascular beds and is thus capable of affecting the systemic circulation, especially the gastrointestinal circulation, in horses. ...
... The mesentery was fixed in formalin, dehydrated with alcohol, and soaked in methyl salicylate to prepare transparent specimens. Histological examination was performed on serial paraffin wax sections of the arterial segments in which a moniliform morphology was observed under a dissecting microscope ( Fig. 1; Oikawa and Shiga, 2002). The stains used were haematoxylin and eosin (HE), elastica van Gieson (EVG), colloidal iron, Mallory's stain, phosphotungstic acid -haematoxylin (PTAH), Congo red and alcian blue (pH 2.5) -periodic acid-Schiff (ABPAS). ...
... The horse's death was considered to be caused by acute endotoxaemia associated with absorption of endotoxin from peritoneal fluid contaminated with gastro-intestinal contents. This assumption was based on the high endotoxin concentrations and the clinical and pathological resemblance to experimental equine endotoxaemia (Oikawa and Shiga, 2002;Oikawa and Yamaoka, 2003). The endotoxin concentrations were similar to those reported previously in horses that died of endotoxaemia with colic (King and Gerring, 1988;Fessler et al., 1989). ...
This report describes the mesenteric arteriolar lesions in a Thoroughbred racehorse with endotoxaemia due to colic. The vascular lesions consisted of a striking loss of medial smooth muscle cells, associated with granular cell debris derived from necrosed muscle cells, plasma insudation, erythrocyte infiltration and the deposition of a fibrinoid substance (fibrinoid degeneration) in the entire arterial wall, possibly produced by the infiltration of blood components through endothelial cell junctions into the arterial wall. The morphology of the mesenteric arteriolar necrosis closely resembled that seen in experimental equine endotoxaemia and in horses that died from colic; it also resembled that of Shiga toxin-induced arteriolar lesions in oedema disease of swine and of the arterionecrosis in human cerebral arteries that may lead to hypertensive intracerebral haemorrhage.
... It was determined that the horses had no chance of recovery. A detailed description of the LPS used and administration of sublethal LPS was given previously [15]. As controls, two male Thoroughbred horses, 3 and 4 years of age (horse 3 and horse 4, respectively), which had been withdrawn from racing because of poor performance, were injected with saline solution on two occasions 24 hr apart. ...
... In contrast, horse 2 remained recumbent after the second infusion. At this point, the two horses were sacrificed by an IV overdose of barbiturate, and immediately necropsied [15]. The control animals showed no abnormal signs during the 48 hr period after the first and second infusions of saline solution. ...
... The clinical signs following LPS administration to the two horses included significant increase or decrease of rectal temperature; increase of heart rate and respiratory rate; subsequent shock, as characterized by extreme coldness of the skin of the lower limbs; collapse; cyanosis of visible mucosae; oliguria accompanied by proteinuria; and abnormalities in gastrointestinal function [15]. The initial clinical signs that follow LPS administration may be manifested by the clinical condition of SIRS: two or more signs such as high or low rectal temperature, increased heart rate and respiratory rate, and leukopenia [2,3,5]. ...
To evaluate the biological response of the horse to endotoxemia, a sublethal amount of lipopolysaccharide (LPS) (10 μg/kg) was given to two Thoroughbreds in two doses 24 hr apart. Each infusion initially produced a significant increase or decrease in rectal temperature, an increase in respiratory rate and heart rate, and a marked decrease in white blood cell count (WBC). The horses subsequently showed signs of shock, characterized by extreme coldness of the skin of lower limbs, as well as cyanosis of the visible mucosae, oliguria accompanied by proteinuria, and abnormalities in gastrointestinal function. The clinical signs of equine endotoxemia may be manifested by the clinical condition of the systemic inflammatory response syndrome (SIRS): two or more of the above signs, such as high or low rectal temperature, increased heart rate and respiratory rate, and leukopenia. Pathobiological responses such as a severe decrease in the number of platelets, hypoglycemia, metabolic acidosis, disorders of hemostasis accompanied by cyanosis of the visible mucosal membranes, proteinuria and oliguria, and abnormal gastrointestinal function, may be manifestations of pathobiological conditions ranging from disseminated intravascular coagulation (DIC) to multiple organ dysfunction syndrome (MODS). Therefore, the clinicopathological responses in equine endotoxemia suggest the nature of SIRS elicited by hypercytokinemia progressing into septic shock.
The clinicopathological features of 15 horses diagnosed with non‐strangulating intestinal infarction (NSII) based on identification of focal areas of intestinal necrosis without mesenteric strangulation were reviewed. The mean age at presentation was 16.3 years, median 13 years, and there was no age, sex, or breed predilection. The major presenting clinical signs included: acute colic ≤ 24 h duration in nine horses; diarrhoea, depression, and inappetence in four horses; and low‐grade chronic or recurrent colic, depression, and inappetence in two horses. One horse presented with both acute colic and diarrhoea. Predisposing diseases included colitis or typhlocolitis in five horses and an initial strangulating small intestinal obstruction in three horses, but in seven horses no underlying or predisposing disease was identified. Four cases were managed medically and 11/15 were managed surgically. The most useful diagnostic test was exploratory celiotomy and the only successful treatment was complete resection of the necrotic intestine. Prognosis for survival was poor with a survival rate of only 1/15 (7%). Among the 15 horses, both single and multiple NSII lesions were seen, and they occurred in both the small intestine and large intestines. There was no evidence of Strongylus vulgaris infestation in any of the affected horses.
To evaluate the effects of endotoxin on the morphology of the equine central, autonomic and enteric nervous system and intestinal muscularis, six Thoroughbred horses with experimentally induced endotoxaemia were examined. The lesions in the central nervous system consisted of perivascular oedema around arterioles, suggesting brain oedema, and ring haemorrhages around veins, similar to those in human patients with septic shock. In the cranial mesenteric ganglia, neuronal cell bodies became pink or red, with shrinkage of cytoplasm indicative of ischaemic changes; intramural and perivascular infiltration by erythrocytes and neutrophils occurred around arterioles in the epineurium (acute focal interstitial inflammation). In addition, transmission electron microscopy revealed oedema of the endoneurium and mesoaxon in the nerve fascicles running inside or outside the ganglia. Myenteric neurons showed shrinkage of the cytoplasm with multiple cytoplasmic vacuoles, suggesting ischaemic changes. Oedematous degeneration and coagulation necrosis of smooth muscle cells, with dissociation of the cells, were prominent in the tunica muscularis. It is suggested that arterionecrosis elicited by endotoxin and frequently observed in the autonomic and enteric nervous system and intestinal muscularis, was the result of vasoconstriction or vasospasm.
Lipopolysaccharides at approximate plasma reactivities >3 ng/mL or beta-glucans at >0.5-1 Amicrog/mL are toxic for human blood; lipopolysaccharide interacts with membrane components of susceptible cells (eg, monocytes) activating phospholipase A(2) that destroys the cell membrane. Cell fragments (microparticles or DNA) possess polynegative niches that activate intrinsic hemostasis. Pathologic disseminated intravascular coagulation arises. Blood vessels are obstructed by disseminated thrombi, and vital organ areas become ischemic. Multiorgan failure threatens life of the patient. Diagnosis and therapy of pathologic disseminated intravascular coagulation is of extreme clinical importance. For early diagnosis of pathologic disseminated intravascular coagulation, specific activation markers of coagulation (eg, plasmatic amidolytic thrombin activity) or the plasmatic lipopolysaccharide or glucan reactivity can be measured. A new treatment target might be kallikrein or factor XIIa; 10 to 20 mM arginine is the approximate 50% inhibitory concentration against the contact phase of coagulation. The complex interaction between cell fragments and hemostasis causes pathologic disseminated intravascular coagulation in sepsis.
