Acute Histopathological Changes Research Articles

Transition to Chronic Fibrosis in an Animal Model of Retinal Detachment With Features of Proliferative Vitreoretinopathy.

Proliferative vitreoretinopathy (PVR) is the most common cause of failure of surgically repaired rhegmatogenous retinal detachment (RRD). Chemically induced and cell injection PVR models do not fully simulate the clinical characteristics of PVR in the post-RRD context. There is an unmet need for translational models in which to study mechanisms and treatments specific to RRD-PVR. RRD was induced in adult Dutch Belted rabbits. Posterior segments were fixed or processed for RNA sequencing at 6 hours and 2, 7, 14, and 35 days after induction. Histochemical staining and immunolabeling for glial fibrillary acidic protein, alpha smooth muscle actin, vascular endothelial growth factor receptor 2, CD68, and RPE 65 kDa protein were performed, and labeling intensity was scored. Single cell RNA sequencing was performed. Acute histopathological changes included intravitreal and intraretinal hemorrhage, leukocytic vitritis, chorioretinitis, and retinal rarefaction. Chronic lesions showed retinal atrophy, gliosis, fibrotic subretinal membranes, and epiretinal fibrovascular proliferation. Fibrillar collagen was present in the fibrocellular and fibrovascular membranes in chronic lesions. Moderate to strong labeling of glia and vasculature was detected in chronic lesions. At day 14, most cells profiled by single cell sequencing were identified as Mϋller glia and microglia, consistent with immunolabeling. Expression of several fibrillar collagen genes was upregulated in chronic lesions. Histological and transcriptional features of this rabbit model simulate important features of human RRD-PVR, including the transition to chronic intraretinal and periretinal fibrosis. This animal model of RRD with features of PVR will enable further research on targeted treatment interventions.

Association between acute histopathological changes of rectal walls and late radiation proctitis following radiotherapy for prostate cancer.

The impact of acute histopathological changes (HC) of the rectum on development of late clinical proctitis (LCP) after external radiotherapy (RT) for prostate cancer is poorly explored and was the primary end point of this prospective study. In 70patients, 15HC of early rectal biopsies after RT were identified, whereby RT was conventional 2D RT in 41cases and conformational 3D RT in 29. Associations of HC in anterior and posterior rectal walls (ARW, PRW) with LCP, acute endoscopic (AEP) and acute clinical proctitis (ACP) were statistically evaluated considering as explicative variables the patient general characteristics and the HC. The mean patients' follow-up was 123.5months (24-209). The median prostatic dose was 72 Gy (2 Gy/fraction). For the 41 and 29patients the ARW and PRW doses were 64 and 49 Gy vs. 63 and 50 Gy, respectively. The incidence of LCP ≥ grade 2 at 10years was 12.9%. The univariate (p = 0.02) and Kaplan-Meyer methods (p = 0.007) showed that the gland (or crypts) loss in the ARW was significantly associated with LCP. AEP and ACP occurred in 14.3 and 55.7% of cases. At multivariate level AEP significantly correlated with hemorrhoids (p = 0.014) and neutrophilia in ARW (p = 0.042). Early after RT, substantial gland loss in ARW is predictive of LCP. To reduce this complication with conventional fractionation, we suggest keeping the mean dose to ARW ≤48-52 Gy.

Adherent/invasive capacities of bovine-associated Aerococcus viridans contribute to pathogenesis of acute mastitis in a murine model

Aerococcus viridans, a firmicutes bacteria widespread in the environment, is increasingly isolated from humans and animals, especially cows with mastitis. However, its pathogenicity in the bovine mammary gland is unclear. The objective was to explore pathogenic potential of putative virulent and avirulent A. viridans in murine systemic and intramammary infection and mechanistically in cultured bovine mammary epithelial cells (bMECs). Virulence of 9 strains of A. viridans, isolated from subclinical cases of mastitis, was tested for their ability to kill mice when systemically inoculated. Two A. viridans strains, causing highest and lowest survival rate in mice, were selected further as putative avirulent and virulent strains, respectively. Staphylococcus aureus N305 was used as a positive control. After intramammary inoculation, the virulent strain survived and replicated in the murine mammary gland for 9 d, whereas the avirulent strain was eliminated within 3 d. The virulent strain induced a robust inflammatory reaction in the mammary gland, characterized by acute histopathological changes, increased myeloperoxidase activity and higher expression of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) compared to the avirulent strain. The virulent strain produced CAMP factor and exhibited strong cytotoxic effects (LDH release) and adhering and invasive abilities in contact with bMECs. Adhesion and invasion of virulent strain to bMECs was further confirmed by scanning and transmission electron microscopy; there was severe damage, including cytomembrane disruption, swollen mitochondria and loss of organelles. In conclusion, the putative virulent strain of A. viridans activated a strong neutrophil-based inflammatory response in the mammary gland, attributed to its ability to adhere to and invade mammary epithelium.

Transgenic supplementation of SIRT1 fails to alleviate acute loss of nigrostriatal dopamine neurons and gliosis in a mouse model of MPTP-induced parkinsonism

Background Dopamine (DA) neuron-selective uptake and toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes parkinsonism in humans. Loss of DA neurons via mitochondrial damage and oxidative stress is reproduced by systemic injection of MPTP in animals, which serves as models of parkinsonism and Parkinson’s disease (PD). This study aimed to test whether pan-neural supplementation of the longevity-related, pleiotropic deacetylase SIRT1, which confers partial tolerance to at least three models of stroke and neurodegeneration, could also alleviate MPTP-induced acute pathological changes in nigrostriatal DA neurons and neighboring glia. Results We employed a line of prion promoter-driven Sirt1-transgenic (Sirt1Tg) mice that chronically overexpress murine SIRT1 in the brain and spinal cord. Sirt1Tg and wild-type (WT) male littermates (3‒4 months old) were subjected to intraperitoneal injection of MPTP. Acute histopathological changes in the midbrain and striatum (caudoputamen) were assessed with serial coronal sections triply labeled for tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP), and nuclear DNA. In the substantia nigra pars compacta (SNpc) of the midbrain, the number of TH-positive neurons and the reactive gliosis were comparable between the Sirt1Tg and WT littermates. In the striatum, the relative fluorescence intensity of TH-positive nerve terminals and the level of gliosis did not differ by the genotypes. Conclusions Sirt1Tg and WT littermate mice exhibited comparable acute histopathological reactions to the systemic injection of MPTP, loss of TH-positive neurons and reactive gliosis. Thus, the genetic supplementation of SIRT1 does not confer histologically recognizable protection on nigrostriatal DA neurons against acute toxicity of MPTP.

Transgenic supplementation of SIRT1 fails to alleviate acute loss of nigrostriatal dopamine neurons and gliosis in a mouse model of MPTP-induced parkinsonism.

Background Dopamine (DA) neuron-selective uptake and toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes parkinsonism in humans. Loss of DA neurons via mitochondrial damage and oxidative stress is reproduced by systemic injection of MPTP in animals, which serves as models of parkinsonism and Parkinson's disease (PD). This study aimed to test whether pan-neural supplementation of the longevity-related, pleiotropic deacetylase SIRT1, which confers partial tolerance to at least three models of stroke and neurodegeneration, could also alleviate MPTP-induced acute pathological changes in nigrostriatal DA neurons and neighboring glia. Results We employed a line of prion promoter-driven Sirt1-transgenic (Sirt1Tg) mice that chronically overexpress murine SIRT1 in the brain and spinal cord. Sirt1Tg and wild-type (WT) male littermates (3‒4 months old) were subjected to intraperitoneal injection of MPTP. Acute histopathological changes in the midbrain and striatum (caudoputamen) were assessed with serial coronal sections triply labeled for tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP), and nuclear DNA. In the substantia nigra pars compacta (SNpc) of the midbrain, the number of TH-positive neurons and the reactive gliosis were comparable between the Sirt1Tg and WT littermates. In the striatum, the relative fluorescence intensity of TH-positive nerve terminals and the level of gliosis did not differ by the genotypes. Conclusions Sirt1Tg and WT littermate mice exhibited comparable acute histopathological reactions to the systemic injection of MPTP, loss of TH-positive neurons and reactive gliosis. Thus, the genetic supplementation of SIRT1 does not confer histologically recognizable protection on nigrostriatal DA neurons against acute toxicity of MPTP.

Reducing the Histopathological Changes of Radioiodine to the Lacrimal Glands by a Popular Anti-Oxidant: Lycopene

Purpose of the study: Radioiodine (RAI) has been used for the treatment of hyperthyroidism and well-differentiated thyroid carcinoma for more than 70 years. Lycopene is an anti-oxidant, which is plentiful in red fruits. The purpose of this study was to investigate the possible inhibitory effect of lycopene on the RAI-induced acute histopathological changes in rat lacrimal glands.Methods: In this experimental animal study, 32 rats were randomly divided into three groups. The first group (control group, n = 8) was not given neither 131I nor lycopene, the second group (RAI group, n = 12) was administrated a single dose of 3 mCi 131I and 1 cc physiologic saline by gastric gavage. The third group (lycopene group, n = 12) was administrated 3 mCi 131I and 1 cc lycopene by gastric gavage. After 24 h of the last dose, the animals were decapitated on the seventh day and their lacrimal glands were removed for histopathological examination.Results: The cell shape and the cell size variation and poorly defined acidophilic cell outlines in all lacrimal glands were observed significantly less frequently in the lycopene group than in the RAI group.Conclusions: Our histopathological examinations have revealed that lycopene prevents rat lacrimal glands against RAI-related acute histopathological changes.

A Novel Swine Model to Evaluate Arterial Vessel Injury after Mechanical Endovascular Thrombectomy

Few animal models have been reported to evaluate and compare mechanical endovascular thrombectomy (MET) devices used to treat human ischemic stroke. These models may contribute to the understanding of arterial injury induced by a MET device and potentially by extrapolation to human intracranial arteries. We have developed a novel swine model for MET that allows visualization of the thrombus/device interaction and characterization of mechanical impact on the vessel wall. Twenty superficial femoral arteries were occluded with radiopaque thrombus, and 20 without thrombus were treated with thrombectomy devices. Acute histopathological changes were evaluated. The swine femoral artery, which is comparable in size to the human middle cerebral artery or basilar artery, may offer a useful animal model for the study of histologic alterations induced by MET.

Histopathologic Evaluation of Arterial Wall Response to 5 Neurovascular Mechanical Thrombectomy Devices in a Swine Model

Five commercial devices are available for mechanical thrombectomy in acute ischemic stroke. This study evaluated and compared the resultant arterial damage from these devices. Wall damage after 4 wall-contact devices (the Merci retriever, Catch thromboembolectomy system, and Solitaire FR revascularization devices of 4 and 6 mm) and 1 aspiration device (the Penumbra System) was evaluated in the superficial femoral arteries of 20 male swine. Each device was tested with and without intraluminal clot. Twenty control vessels were not subjected to any intervention. Acute histopathologic changes were evaluated. In the device samples, endothelial denudation (72.8 ± 29.4% versus 0.9 ± 1.9%, P < .0001), medial layer edema (52 ± 35.9% versus 18.1 ± 27.8%, P = .004), and mural thrombus (5.3 ± 14.2% versus 0%, P = .05) were found to a greater extent compared with the control samples. The aspiration device provoked more intimal layer (100 ± 79.1% versus 58.8 ± 48.9%, P = .27) and medial layer (75 ± 35.4% versus 46.3 ± 34.8%, P = .13) edema than the wall-contact devices. All devices caused vascular injuries extending into the medial layer. The aspiration device was associated with more intimal and medial layer edema, compared with the wall-contact devices except for the Catch thromboembolectomy system.

Hyaluronic acid–paclitaxel conjugate inhibits growth of human squamous cell carcinomas of the head and neck via a hyaluronic acid-mediated mechanism

Chemotherapeutic regimens incorporating taxanes significantly improve outcomes for patients with squamous cell carcinomas of the head and neck (SCCHN). However, treatment with taxanes is limited by toxicities, including bone marrow suppression and peripheral neuropathies. We proposed that conjugating taxanes to targeting carrier molecules would increase antitumor efficacy and decrease toxicity. The cell surface proteoglycan, CD44, is expressed on most SCCHNs, and we hypothesized that it is an attractive candidate for targeted therapy via its natural ligand, hyaluronic acid (HA). We determined whether HA-paclitaxel conjugates were able to decrease tumor growth and improve survival in orthotopic nude mouse human SCCHN xenograft models. HA-paclitaxel concentration-dependent growth inhibition of human SCCHN cell lines OSC-19 and HN5 in vitro, very similarly to free paclitaxel treatment. Tumor cell uptake of FITC-labeled HA-paclitaxel was significantly blocked with free HA, indicating the dependence of uptake on CD44. HA-paclitaxel administered intravenously once per week for three weeks at 120 mg/kg paclitaxel equivalents, far above the paclitaxel maximum tolerated dose, exerted superior tumor growth control to that of paclitaxel in both orthotopic OSC-19-luciferase and HN5 xenograft models in vivo. Mouse survival following HA-paclitaxel administration was prolonged compared with that of controls in mice implanted with either of these xenografts. Mice treated with HA-paclitaxel displayed increased TUNEL(+) cells in tumor tissue, as well as markedly reduced microvessel density compared to those treated with free paclitaxel. No acute histopathological changes were observed in mice treated with HA-paclitaxel. Thus, we conclude that HA-paclitaxel effectively inhibits tumor growth in human SCCHN xenografts via an HA-mediated mechanism and this conjugate should be considered for further preclinical development for this disease.

Histological and haematotoxic effects of Azadirachta indica (Neem) leaf extract in albino rats

The crude methanolic extract of Azadirachta indica leaves was administered intraperitoneally once daily for ten days at varied doses of (100, 200 and 500mg/kg) in 24 albino rats. The acute histopathological changes induced in the spleen, liver, kidney, heart and lungs of the albino rats were studied. Changes in serum biochemical and haematological parameters were also studied [1]. The histopathological results showed congestion and haemosiderosis at a dose level of 200mg/kg, while sections of the lungs showed evidence of interstitial pneumonia and interlobular oedema, the hepatocytes showed necrosis, margination of nuclear chromatin and hyperplastic bile duct epithelial cells. The control group (0mg/kg) and 100mg/kg treatment groups had no lesion. It was then concluded that the administration of the extracts to the rats at doses of 200mg/kg i.p and above, induces histological changes in the spleen, liver and lung which are dose dependent. On the haematotoxic effects, administration of the extract at a dose level of 100mg/kg did not produce any toxic symptoms but at 200 and 500mg/kg, the animals showed high incidence of mortality, even though no significant difference in weight gain, food consumption and fluid intake was observed. There was a fall in packed cell volume (PCV) and a significant elevation of total leucocyte (WBC) count serum trasaminases (ALT and AST) showed enhanced activity and there was an elevation in the levels of urea and bilirubin. Hence, the extracts suggest haematotoxicity in rats at the doses of 200 and 500mg/kg bwt.

External cardiac defibrillation does not cause acute histopathological changes typical of thermal injuries in pigs with in situ cerebral stimulation electrodes.

Parkinson's disease patients with long-term L-dopa syndrome may benefit from an implanted cerebral stimulation device. When advanced life support demands cardioversion or defibrillation in these patients, undesired effects of monophasic electroshocks might occur in brain tissue adjacent to the stimulation electrodes (e.g., thermal injury), but also in the stimulation device itself. Thus, in this animal study (n = 6 pigs), we investigated the effects of repeated defibrillation (2 x 200 J [n = 1] and 2 x 360 J [n = 5]) at the implantation site of cerebral stimulation electrodes and on stimulation device function. Repeated external cardiac defibrillation did not cause acute histopathologic changes typical of thermal injury to brain tissue adjacent to the cerebral stimulation electrodes. Functionality of the stimulator device after defibrillation, however, ranged from normal to total loss of function. Therefore, when defibrillation is performed, the greatest possible distance between the defibrillation site and the stimulator device implantation site should be considered. Subsequent testing of the stimulator device's function is mandatory. Repeated cardiac defibrillation did not cause histopathologic changes typical of thermal injury at the implantation site of cerebral stimulation electrodes. The function of the stimulator device after defibrillation, however, ranged from normal to total loss of function.

Does apoptosis cause renal atrophy in Balkan endemic nephropathy?

The aetiology of Balkan endemic nephropathy continues to defy explanation, although the nephrotoxic mycotoxin ochratoxin A may be involved.1 However, the toxicity profile of ochratoxin A does not easily fit with the slowly progressive and symptomless atrophy of the kidneys that occurs. A common food spoilage mould in the Balkans, Penicillium polonicum (formerly P aurantiogriseum), induces acute histopathological changes in the P3 segment of the nephrons of Sprague-Dawley rats given for 5 days, or less, a diet containing shredded wheat moulded by this fungus.

Comparative toxicity of methyl isocyanate and its hydrolytic derivatives in rats. I. Pulmonary histopathology in the acute phase.

The present study describes the acute histopathological changes induced by methyl isocyanate (MIC) in the lungs of rats at 24 h after a single exposure to varied concentrations/doses of MIC by inhalation and subcutaneous (s.c.) routes and also delineates the effects due to the hydrolytic derivatives of MIC, viz., methylamine (MA) and N,N'-dimethyl urea (DMU). MIC, either inhaled or administered s.c., resulted in a wide range and extent of histopathological changes in the lungs, proportional to the exposure concentration/dose. The salient, effects of inhaled MIC are acute necrotizing bronchitis of the entire respiratory tract accompanied by varying degrees of confluent congestion, hyperemia and interstitial and intra-alveolar edema, while MIC administered s.c. led to prominent vascular endothelial damage, congestion and severe interstitial pneumonitis with apparently normal bronchial epithelium; and intra-alveolar edema only with the high dose. The only noteworthy lesion produced by MA and DMU (to some extent) was interstitial pneumonitis, suggesting their possible involvement in the subsequent inflammatory response of MIC. Except, for the endothelial changes, the overall spectrum of the histopathological lesions is quite comparable to those observed in the lungs of Bhopal victims during the acute phase.

Kainic acid-induced seizures: Dose-relationship of behavioural neurochemical and histopathological changes

Behavioural, neurochemical and histopathological changes induced by systemic injection of kainic acid were investigated at various doses of the neurotoxin (3, 6 and 10 mg/kg s.c.). There was a positive correlation between the dose of kainic acid and the extent of both the acute neurochemical changes 3 h after the injection (increases of 3, 4-dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid levels and a decrease in noradrenaline levels in all brain regions investigated), the acute histopathological changes (shrinkage and condensation of nerve cells and brain oedema in the entire forebrain) and the extent of behavioural alterations (immobility, ‘wet dog shakes’ and limbic seizures). However, the slope of the dose-response curves was very steep. Late and irreversible alterations included losses of the enzyme markers glutamic acid decar☐ylase and choline acetyltransferase and, histopathologically, incomplete parenchymal necrosis and haemorrhages. These changes, however, were restricted to a few brain regions, the most important being the hippocampus, amygdala, entorhinal and pyriform cortex, and olfactory bulb, and they were seen only in animals which had undergone severe convulsions. It is suggested that the irreversible brain lesions in this animal model of limbic (temporal lobe) epilepsy are not solely induced by a direct action of kainic acid, but may be caused — at least in part — by additional, secondary pathogenetic mechanisms.

THE TRANSPLANTED RAT HEART: HISTOLOGIC AND ELECTROCARDIOGRAPHIC CHANGES.

In a study of ectopically transplanted rat hearts, all grafts showed minimal acute epicarditis and transient electrocardiographic patterns of injury for 24 to 48 hours. Isografts showed no further acute histopathologic changes and had relatively normal electrocardiograms for as long as 290 days. First-set homografts had subendocardial and perivascular mononuclear-cell infiltration three days after transplantation. By the fifth day, generalized mononuclear cell infiltration of the myocardium, interstitial edema, and vascular endothelial edema were evident; electrocardiograms at this time were similar to those of the isografts. Within 7 to 8 days, homografts showed extensive myocardial necrosis although cellular infiltration had lessened. Vascular edema was more prominent but fibrinoid necrosis was not observed. Electrocardiograms, which differed from those of the isografts, showed flattened T waves and defective intraventricular conduction. Electrical activity was lost 9 to 13 days after transplantation. Grafts placed in sensitized hosts had extensive mononuclear-cell infiltration of the subendocardium and myocardium, interstitial edema, and vascular endothelial edema three days after transplantation. Electrocardiograms showed flattened T waves and defective intraventricular conduction 4 to 6 days after transplantation, and electrical activity was lost within 5 to 10 days. For 2 to 5 days preceding loss of electrical activity, therefore, homografts had a specific electrocardiographic pattern which could be used as a precise criterion of rejection.