Unconjugated Bilirubin Contributes to Early Inflammation and Edema after Intracerebral Hemorrhage

Loftspring, Matthew C.; Johnson, Holly L.; Feng, Rui; Johnson, Aaron J.; Clark, Joseph F.

doi:10.1038/jcbfm.2010.203

Cited by 39 publications

(30 citation statements)

References 40 publications

(54 reference statements)

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“…Hemoglobin, which is released when erythrocytes lyse in the hematoma, is also a potent activator of microglia via toll-like receptors (TLRs) (Wang et al, 2014; Zhou et al, 2014b). Bilirubin, a hemoglobin breakdown product, can also induce neutrophil extravasation into brain but does not activate microglia (Loftspring et al, 2011). …”

Section: Role Of Intercellular and Hematoma:cell Signaling In Ich-mentioning

confidence: 99%

Intercellular cross-talk in intracerebral hemorrhage

et al. 2015

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Intracerebral hemorrhage (ICH) is a devastating cerebrovascular disorder with high mortality and morbidity. Currently, there are few treatment strategies for ICH-induced brain injury. A recent increase in interest in the pathophysiology of ICH, has led to elucidation of the pathways underlying ICH-induced brain injury, pathways where intercellular and hematoma to cell signaling play important roles. In this review, we summarize recent advances in ICH research focusing on intercellular and hematoma:cell cross-talk related to brain injury and recovery after ICH.

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Section: Role Of Intercellular and Hematoma:cell Signaling In Ich-mentioning

confidence: 99%

Intercellular cross-talk in intracerebral hemorrhage

et al. 2015

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“…4,5 Intercellular adhesion molecule-1 (ICAM-1) has been reported to be a potential factor facilitating increased neutrophil infiltration into the brain parenchyma after ICH. 6,7 Vascular smooth muscle cells (VSMC) are key components of the vascular neural network and play an important role in stroke pathophysiology. 8 VSMC marker proteins are commonly used to define the VSMC phenotype, whereas α-smooth muscle actin (α-SMA) is a typical marker protein of all smooth muscle, and Non-Muscle Myosin IIB (SMemb) and ICAM-1 are the marker proteins for the VSMC synthetic phenotype.…”

Section: Introductionmentioning

confidence: 99%

Platelet-Derived Growth Factor Receptor-β Regulates Vascular Smooth Muscle Cell Phenotypic Transformation and Neuroinflammation After Intracerebral Hemorrhage in Mice

Yang

Miao

et al. 2016

Critical Care Medicine

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Objective Platelet-derived growth factor-BB (PDGF-BB) activates platelet-derived growth factor receptor-β (PDGFR-β) and promotes vascular smooth muscle cell phenotypic transformation. Elevated levels of non-muscle myosin IIB (SMemb) are found in secretory smooth muscle cells along with inflammatory mediators, such as intercellular adhesion molecule-1 (ICAM-1), which can amplify neutrophil infiltration into the brain. In the present study, we investigated the role of PDGF-BB/PDGFR-β following intracerebral hemorrhage (ICH)-induced brain injury in mice, with emphasis on its ability to promote vascular smooth muscle cell (VSMC) phenotypic transformation followed by increased ICAM-1 expression and elevated neutrophil infiltration in the vicinity of the hematoma. We also determined the extent to which plasmin from the hematoma influences the PDGF-BB/PDGFR-β system subsequent to ICH. Methods Brain injury was induced by autologous arterial blood (bICH) or plasmin injection into mouse brains. Small interfering RNA targeting PDGFR-β was administered 24 hours before ICH. A PDGFR antagonist, Gleevec, was administered following ICH. A mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2, MK2) inhibitor (KKKALNRQLGVAA) was delivered with PDGF-BB in naïve animals. PDGF-BB was injected with a plasmin inhibitor (ɛ-Aminocaproic acid, EACA) in ICH mice. Plasmin-injected mice were given PDGFR-β small interfering RNA 24 hours before the operation. Neurological deficits, brain edema, Western blots and immunofluorescence were evaluated. Results PDGFR-βsiRNA-attenuated SMemb and ICAM-1 expression and neutrophil infiltration at 24 hours post-injury, and reduced neurological deficits and brain edema at 24 and 72 hours following ICH. The PDGFR antagonist, Gleevec, reduced SMemb and ICAM-1 expression. PDGFR-β activation led to increased expression of ICAM-1 and was reversed by KKKALNRQLGVAA in naïve mice. Plasmin inhibition suppressed PDGFR-β activation and neutrophil infiltration, whereas exogenous PDGF-BB increased PDGFR-β activation, regardless of plasmin inhibition. PDGFR-β siRNA decreased the expression of ICAM-1 by plasmin injection. Interpretation The PDGF-BB/PDGFR-β system contributes to neuro-inflammation through VSMC phenotypic transformation near the hematoma via the p38 MAPK/MK2 pathway following ICH. Plasmin is hypothesized to be upstream of the proposed neuro-inflammatory system. The therapeutic intervention targeting the PDGF-BB/PDGFR-β is a novel strategy to prevent plasmin-induced brain injury following ICH.

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“…To detect the specific types of cells expressing CD36 in perihematomal tissues, single-cell suspensions of perihematomal tissues were prepared as described previously (16,26). Briefly, after the mice were anesthetized with chloral hydrate, cardiac perfusion was performed using cold sterile PBS; the left brain was then removed immediately, placed in a C-tube (Miltenyi Biotec, Bergisch Gladbach, Germany), mixed with lysis buffer, and ground in a gentleMACS dissociator (Miltenyi Biotec).…”

Section: Flow Cytometrymentioning

confidence: 99%

CD36-Mediated Hematoma Absorption following Intracerebral Hemorrhage: Negative Regulation by TLR4 Signaling

Huang

Chen

Lin

et al. 2014

The Journal of Immunology

113

112

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Promoting hematoma absorption is a novel therapeutic strategy for intracerebral hemorrhage (ICH); however, the mechanism of hematoma absorption is unclear. The present study explored the function and potential mechanism of CD36 in hematoma absorption using in vitro and in vivo ICH models. Hematoma absorption in CD36-deficient ICH patients was examined. Compared with patients with normal CD36 expression, CD36-deficient ICH patients had slower hematoma adsorption and aggravated neurologic deficits. CD36 expression in perihematomal tissues in wild-type mice following ICH was increased, whereas the hematoma absorption in CD36−/− mice was decreased. CD36−/− mice also showed aggravated neurologic deficits and increased TNF-α and IL-1β expression levels. The phagocytic capacity of CD36−/− microglia for RBCs was also decreased. Additionally, the CD36 expression in the perihematoma area after ICH in TLR4−/− and MyD88−/− mice was significantly increased, and hematoma absorption was significantly promoted, which was significantly inhibited by an anti-CD36 Ab. In vitro, TNF-α and IL-1β significantly inhibited the microglia expression of CD36 and reduced the microglia phagocytosis of RBCs. Finally, the TLR4 inhibitor TAK-242 upregulated CD36 expression in microglia, promoted hematoma absorption, increased catalase expression, and decreased the H2O2 content. These results suggested that CD36 mediated hematoma absorption after ICH, and TLR4 signaling inhibited CD36 expression to slow hematoma absorption. TLR4 inhibition could promote hematoma absorption and significantly improve neurologic deficits following ICH.

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Unconjugated Bilirubin Contributes to Early Inflammation and Edema after Intracerebral Hemorrhage

Cited by 39 publications

References 40 publications

Intercellular cross-talk in intracerebral hemorrhage

Intercellular cross-talk in intracerebral hemorrhage

Platelet-Derived Growth Factor Receptor-β Regulates Vascular Smooth Muscle Cell Phenotypic Transformation and Neuroinflammation After Intracerebral Hemorrhage in Mice

CD36-Mediated Hematoma Absorption following Intracerebral Hemorrhage: Negative Regulation by TLR4 Signaling

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