Glial scars are permeable to the neurotoxic environment of chronic stroke infarcts.

Following stroke, the damaged tissue undergoes liquefactive necrosis, a stage of infarct resolution that lasts for months although the exact length of time is currently unknown. One method of repair involves reactive astrocytes and microglia forming a glial scar to compartmentalize the area of liquefactive necrosis from the rest of the brain. The formation of the glial scar is a critical component of the healing response to stroke, as well as other central nervous system (CNS) injuries. The goal of this study was to evaluate the toxicity of the extracellular fluid present in areas of liquefactive necrosis and determine how effectively it is segregated from the remainder of the brain. To accomplish this goal, we used a mouse model of stroke in conjunction with an extracellular fluid toxicity assay, fluorescent and electron microscopy, immunostaining, tracer injections into the infarct, and multiplex immunoassays. We confirmed that the extracellular fluid present in areas of liquefactive necrosis following stroke is toxic to primary cortical and hippocampal neurons for at least 7 weeks following stroke, and discovered that although glial scars are robust physical and endocytic barriers, they are nevertheless permeable. We found that molecules present in the area of liquefactive necrosis can leak across the glial scar and are removed by a combination of paravascular clearance and microglial endocytosis in the adjacent tissue. Despite these mechanisms, there is delayed atrophy, cytotoxic edema, and neuron loss in regions adjacent to the infarct for weeks following stroke. These findings suggest that one mechanism of neurodegeneration following stroke is the failure of glial scars to impermeably segregate areas of liquefactive necrosis from surviving brain tissue.

A radiological footprint equivalent to liquefactive necrosis observed in the course of disappearing liver metastases in rectal cancer: A case report and review of the literature.

A 72-year-old female diagnosed with rectal cancer treated with a surgical procedure was reported. As 3 liver metastases (LMs) appeared in multidetector CT, adjuvant chemotherapy using Bevacizumab combined with modified FOLFOX-6 was completed. LMs were changed to cystic lesions during the follow-up period, consistent with liquefactive necrosis. These cystic lesions that appeared in the course of disappearing LMs (DLMs) were identified by CT as homogeneous low signal intensity in hepatocyte specific Gd-enhanced MRI. This might be pathognomonic radiological footprint equivalent to liquefactive necrosis observed in the process of DLM and must be carefully followed in the course of radiological complete response. The radiological changing findings of LMs to cystic changes, high sensitivity of detecting DLM, and limitations of Gd-MRI might be meaningful to clinicians.

Increased Liquefactive Necrosis Formation After Transarterial Chemoembolization Combined with Molecular Targeted Agents Plus Immune Checkpoint Inhibitors for Hepatocellular Carcinoma.

PURPOSE: In clinical practice, we found some of the patients who received transarterial chemoembolization (TACE) with molecular targeted agents (MTGs) plus immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) had obvious liquefactive necrosis formation within the tumor and some even progressed to a liver abscess, which seems more frequent than patients who received other treatments. Thus, we aim to identify this condition and analyze the potential risk factors. PATIENTS AND METHODS: Medical records of 72 consecutive patients with intermediate (BCLC B) and advanced (BCLC C) HCC who received TACE plus MTGs combined with (n=30) or without (n=42) ICIs were reviewed. Liquefactive necrosis formation was defined as the presence of obvious liquefactive necrosis within the tumor that required intervention. RESULTS: The liquefactive necrosis rate was higher in the TACE+MTGs+ICIs group than in the TACE+MTGs group (30% vs 4.8%, P=0.006). Moreover, 18.2% (2/11) of the patients with liquefactive necrosis within the tumor had a bacterial infection. We then take the binary logistic regression analysis model to identify the predictors of liquefactive necrosis formation, and which showed the tumor size (P=0.006, OR=1.355, 95% CI: 1.090-1.684), alpha-fetoprotein level (P=0.036, OR=6.745, 95% CI: 1.130-40.262) and treatment modality (P=0.015, OR=11.717, 95% CI: 1.617-84.887) were the independent risk factor for liquefactive necrosis formation within the tumor. CONCLUSION: Patients with HCC who received TACE combined with MTGs plus ICIs have increased liquefactive necrosis formation, and the larger tumor size and higher alpha-fetoprotein level were associated with more liquefactive necrosis formation within the tumor.

Liquefaction of the Brain following Stroke Shares a Similar Molecular and Morphological Profile with Atherosclerosis and Mediates Secondary Neurodegeneration in an Osteopontin-Dependent Mechanism.

Here we used mouse models of heart and brain ischemia to compare the inflammatory response to ischemia in the heart, a protein rich organ, to the inflammatory response to ischemia in the brain, a lipid rich organ. We report that ischemia-induced inflammation resolves between one and four weeks in the heart compared to between eight and 24 weeks in the brain. Importantly, we discovered that a second burst of inflammation occurs in the brain between four and eight weeks following ischemia, which coincided with the appearance of cholesterol crystals within the infarct. This second wave shares a similar cellular and molecular profile with atherosclerosis and is characterized by high levels of osteopontin (OPN) and matrix metalloproteinases (MMPs). In order to test the role of OPN in areas of liquefactive necrosis, OPN-/- mice were subjected to brain ischemia. We found that at seven weeks following stroke, the expression of pro-inflammatory proteins and MMPs was profoundly reduced in the infarct of the OPN-/- mice, although the number of cholesterol crystals was increased. OPN-/- mice exhibited faster recovery of motor function and a higher number of neuronal nuclei (NeuN) positive cells in the peri-infarct area at seven weeks following stroke. Based on these findings we propose that the brain liquefies after stroke because phagocytic cells in the infarct are unable to efficiently clear cholesterol rich myelin debris, and that this leads to the perpetuation of an OPN-dependent inflammatory response characterized by high levels of degradative enzymes.

Multiplex immunoassay characterization and species comparison of inflammation in acute and non-acute ischemic infarcts in human and mouse brain tissue.

This study provides a parallel characterization of the cytokine and chemokine response to stroke in the human and mouse brain at different stages of infarct resolution. The study goal was to address the hypothesis that chronic inflammation may contribute to stroke-related dementia. We used C57BL/6 and BALB/c mice to control for strain related differences in the mouse immune response. Our data indicate that in both mouse strains, and humans, there is increased granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin-6 (IL-6), interleukin-12 p70 (IL-12p70), interferon gamma-induced protein-10 (IP-10), keratinocyte chemoattractant/interleukin-8 (KC/IL-8), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), macrophage inflammatory protein-1ß (MIP-1ß), regulated on activation, normal T cell expressed and secreted (RANTES), and Tumor necrosis factor-α (TNF-α) in the infarct core during the acute time period. Nevertheless, correlation and two-way ANOVA analyses reveal that despite this substantial overlap between species, there are still significant differences, particularly in the regulation of granulocyte colony-stimulating factor (G-CSF), which is increased in mice but not in humans. In the weeks after stroke, during the stage of liquefactive necrosis, there is significant resolution of the inflammatory response to stroke within the infarct. However, CD68+ macrophages remain present, and levels of IL-6 and MCP-1 remain chronically elevated in infarcts from both mice and humans. Furthermore, there is a chronic T cell response within the infarct in both species. This response is differentially polarized towards a T helper 1 (Th1) response in C57BL/6 mice, and a T helper 2 (Th2) response in BALB/c mice, suggesting that the chronic inflammatory response to stroke may follow a different trajectory in different patients. To control for the fact that the average age of the patients used in this study was 80 years, they were of both sexes, and many had suffered from multiple strokes, we also present findings that reveal how the chronic inflammatory response to stroke is impacted by age, sex, and multiple strokes in mice. Our data indicate that the chronic cytokine and chemokine response to stroke is not substantially altered in 18-month old compared to 3-month old C57BL/6 mice, although T cell infiltration is attenuated. We found a significant correlation in the chronic cytokine response to stroke in males and females. However, the chronic cytokine response to stroke was mildly exacerbated by a recurrent stroke in both C57BL/6 and BALB/c mice.

Irritants and corrosives.

This article reviews toxic chemicals that cause irritation and damage to single and multiple organ systems (corrosion) in an acute fashion. An irritant toxic chemical causes reversible damage to skin or other organ system, whereas a corrosive agent produces irreversible damage, namely, visible necrosis into integumentary layers, following application of a substance for up to 4 hours. Corrosive reactions can cause coagulation or liquefaction necrosis. Damaged areas are typified by ulcers, bleeding, bloody scabs, and eventual discoloration caused by blanching of the skin, complete areas of alopecia, and scars. Histopathology should be considered to evaluate questionable lesions.