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Biomedical subjects

Johann S Braun

Publications and source records attributed to Johann S Braun.

11 recordsLinked to original sources
PubMed2006

Stroke propagates bacterial aspiration to pneumonia in a model of cerebral ischemia.

BACKGROUND AND PURPOSE: Bacterial pneumonia is the most common cause of death in patients sustaining acute stroke and is believed to result from an increased aspiration. Recently, stroke-induced immunodeficiency was described in a mouse model of cerebral ischemia, which is primarily caused by overactivation of sympathetic nervous system. We tested if stroke-induced immunodeficiency increases the risk of pneumonia after aspiration in a newly developed model of poststroke pneumonia. METHODS: Experimental stroke in mice was induced by occlusion of the middle cerebral artery (MCAO) for 60 minutes. Aspiration pneumonia was induced by intranasal application of 20 microL of a defined suspension of Streptococcus pneumoniae in phosphate-buffered saline 4 or 14 days after MCAO. Treatment comprised moxifloxacin (100 mg/kg body weight, six times every 2 hours after operation) or propranolol (30 mg/kg body weight, immediately before as well as 4 and 8 hours after MCAO). Readout was lung histology and bacterial counts in lung and blood. RESULTS: Nasal inoculation of only 200 colony-forming units of S. pneumoniae caused severe pneumonia and bacteremia after experimental stroke, whereas 200,000 colony-forming units are needed to induce comparable disease in sham animals. Aspiration pneumonia in stroke animals outlasted acute stroke state but was preventable by beta-adrenoreceptor blockade. CONCLUSIONS: Experimental stroke propagates bacterial aspiration from harmless intranasal colonization to harmful pneumonia. Prevention of infections by beta-adrenoreceptor blockade suggests that immunodepression by sympathetic hyperactivity is essential for progression of bacterial aspiration to pneumonia.

Acute Disease↗
PubMed2005

Nitric oxide modulates calcium entry through P/Q-type calcium channels and N-methyl-d-aspartate receptors in rat cortical neurons.

Voltage-gated calcium channels (VGCC) and N-methyl-d-aspartate receptors (NMDAR) account for most of the depolarization-induced neuronal calcium entry. The susceptibility of individual routes of calcium entry for nitric oxide (NO) is largely unknown. We loaded cultured rat cortical neurons with fluo-4 acetoxymethylester to study the effect of the NO synthase inhibitor Nomega-nitro-l-arginine and the NO donor S-nitroso-N-acetylpenicillamine on the intracellular calcium concentration ([Ca2+]i). The potassium-induced [Ca2+]i increase was amplified by Nomega-nitro-l-arginine and attenuated by S-nitroso-N-acetylpenicillamine. This modulation was abolished by either the P/Q-type VGCC antagonist omega-agatoxin IVA or by the NMDAR antagonist MK-801, but not by N-type (omega-conotoxin GVIA) or L-type (nimodipine) VGCC blockers. These results suggest that NO can modulate neuronal calcium entry during depolarization by interacting with P/Q-type VGCC and NMDAR.

Action Potentials↗
PubMed2005

Bacterial programmed cell death of cerebral endothelial cells involves dual death pathways.

Major barriers separating the blood from tissue compartments in the body are composed of endothelial cells. Interaction of bacteria with such barriers defines the course of invasive infections, and meningitis has served as a model system to study endothelial cell injury. Here we report the impressive ability of Streptococcus pneumoniae, clinically one of the most important pathogens, to induce 2 morphologically distinct forms of programmed cell death (PCD) in brain-derived endothelial cells. Pneumococci and the major cytotoxins H2O2 and pneumolysin induce apoptosis-like PCD independent of TLR2 and TLR4. On the other hand, pneumococcal cell wall, a major proinflammatory component, causes caspase-driven classical apoptosis that is mediated through TLR2. These findings broaden the scope of bacterial-induced PCD, link these effects to innate immune TLRs, and provide insight into the acute and persistent phases of damage during meningitis.

Animals↗
PubMed2004

Dual phases of apoptosis in pneumococcal meningitis.

Significant injury during bacterial meningitis arises from mechanisms of neuronal apoptosis, particularly in the hippocampus. Apoptosis can involve both the caspase-dependent and the caspase-independent pathway, and, although both pathways have been implicated in pneumococcus-induced neuronal cell death, their relative contributions in vivo are unclear. We used mice deficient in the activation of caspase-3, ATM, and p53 to examine the role that caspase-dependent apoptosis plays in neuronal death in the context of pneumococcal meningitis. The overall symptomatology of acute infection was similar in all mice tested, indicating that late sequelae are the clinical manifestations of neuronal death. Two phases of apoptosis were discernible: neuronal injury at 18 h after infection was independent of the caspase-3 pathway, and neuronal cell death at 24 h after infection was attenuated in the absence of the caspase-3 pathway. We conclude that treatments to increase the survival rate of neurons in patients with meningitis will need to take into account at least these 2 mechanisms of damage.

Animals↗
PubMed2004

Neuronal gelsolin prevents apoptosis by enhancing actin depolymerization.

Gelsolin (gsn), an actin-severing protein, protects neurons from excitotoxic cell death via inactivation of membranous Ca(2+) channels. Its role during apoptotic cell death, however, has remained unclear. Using several models of neuronal cell death, we demonstrate that endogenous gelsolin has anti-apoptotic properties that correlate to its dynamic actions on the cytoskeleton. We show that neurons lacking gelsolin (gsn(-/-)) have enhanced apoptosis following exposure to staurosporine, thapsigargin, or the cholinergic toxin ethylcholine aziridinium (AF64A). AF64A-induced loss of mitochondrial membrane potential and activation of caspase-3 was specifically enhanced in gsn(-/-) neurons and could be reversed by pharmacological inhibition of mitochondrial permeability transition. Moreover, increased caspase-3 activation and cell death in AF64A-treated gsn(-/-) neurons were completely reversed by pharmacological depolymerization of actin filaments and further enhanced by their stabilization. In conclusion, actin remodeling by endogenous gelsolin or analogues protects neurons from apoptosis mediated by mitochondria and caspase-3.

Actin Cytoskeleton↗
PubMed2002

Group B streptococcal beta-hemolysin induces mortality and liver injury in experimental sepsis.

New Zealand White rabbits were challenged with the wild-type (wt) group B streptococci (GBS) serotype III strain (COH1) and its isogenic nonhemolytic (NH) and hyperhemolytic (HH) mutants. Mortality differed significantly between rabbits infected with the HH mutant IN40 (67%), compared with rabbits infected with the wt COH1 strain (27%) and the NH strains COH1-20 and COH1:cylEDeltacat (13% and 0%, respectively; P<.05). Histopathologically, disseminated septic microabscesses surrounded by necrotic foci were found exclusively in the livers of HH mutant IN40-infected animals. Serum transaminase levels were 20-fold higher in the HH-infected group, compared with rabbits infected with the other strains. Positive TUNEL (in situ terminal deoxynucleotide transferase-mediated dUTP nick end labeling) staining and activation of caspase-3 in hepatocytes were more frequent in HH-infected than in wt-infected animals and absent in the NH mutant COH1-20-infected group, indicating that GBS beta-hemolysin triggers apoptotic pathways in hepatocytes. This work provides the first evidence that GBS beta-hemolysin plays a crucial role in the pathophysiology of GBS sepsis by inducing liver failure and high mortality.

Animals↗
PubMed2002

Differential post-transcriptional regulation of p21WAF1/Cip1 levels in the developing nervous system following gamma-irradiation.

Radiation-induced death in the developing brain is p53-dependent. However, genetic studies indicate that the signalling pathways that couple irradiation to p53 expression can vary between different developing neural populations [Herzog et al. (1998) Science, 280, 1089-1091]. Here we establish that signalling downstream of p53 also exhibits brain region-specific differences that are associated with the relative vulnerability of some cell populations to radiation-induced killing in the mouse. Following gamma-irradiation, p53 and p21WAF1/cip1, but not Bax, protein levels increased in the developing cerebellum. In contrast, neither p21WAF1/cip1 nor Bax protein levels were elevated in the retina following irradiation, despite increased p53 expression. In the retina, p53 expression was associated with cells destined to die, whereas in the cerebellum, p53 was expressed in both radiation-sensitive and radiation-resistant neuroblasts of the external granule cell layer. Although p21WAF1/cip1 mRNA was expressed in all p53-positive neuroblasts after irradiation, p21WAF1/cip1 protein was only detected in radiation-resistant neuroblasts of the cerebellum. Thus, p21WAF1/cip1 was subject to post-transcriptional regulation with p21WAF1/cip1 protein only accumulating in cells destined to survive irradiation. Nevertheless, p21WAF1/cip1 function was not essential for radiation resistance, as postmitotic neuroblasts in the external granule cell layer were spared in p21WAF1/cip1 knockout mice.

Animals↗
PubMed2002

Pneumococcal pneumolysin and H(2)O(2) mediate brain cell apoptosis during meningitis.

Pneumococcus is the most common and aggressive cause of bacterial meningitis and induces a novel apoptosis-inducing factor-dependent (AIF-dependent) form of brain cell apoptosis. Loss of production of two pneumococcal toxins, pneumolysin and H(2)O(2), eliminated mitochondrial damage and apoptosis. Purified pneumolysin or H(2)O(2) induced microglial and neuronal apoptosis in vitro. Both toxins induced increases of intracellular Ca(2+) and triggered the release of AIF from mitochondria. Chelating Ca(2+) effectively blocked AIF release and cell death. In experimental pneumococcal meningitis, pneumolysin colocalized with apoptotic neurons of the hippocampus, and infection with pneumococci unable to produce pneumolysin and H(2)O(2) significantly reduced damage. Two bacterial toxins, pneumolysin and, to a lesser extent, H(2)O(2), induce apoptosis by translocation of AIF, suggesting new neuroprotective strategies for pneumococcal meningitis.

Animals↗
PubMed2002

Diagnostic pitfall: atypical cerebral venous drainage via the vertebral venous system.

We report a case of atypical cerebral venous drainage in a 38-year-old woman with symptoms of benign paroxysmal positional vertigo. Thrombosis of the left internal jugular vein and sigmoid sinus was suspected on the basis of spin-echo and time-of-flight MR findings, but multisection CT angiograms showed a patent sigmoid sinus and predominant drainage via the emissary veins toward the vertebral plexus, with only a minor contribution of the jugular veins. This case illustrates the variability of the venous anatomy in the craniocervical region.

Adult↗