The Journal of clinical investigation
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The pathobiology of pulmonary arterial hypertension (PAH) includes endothelial cell dysfunction and proliferation and migration of VSMCs. As PDGF has been implicated in these processes, Schermuly et al. hypothesized that altered PDGF signaling may be involved in the vascular remodeling observed in PAH. ⋯ In both models, after development of pulmonary vascular disease, administration of STI571 reversed pulmonary vascular changes. These studies provide preclinical proof of concept for the clinical development of a PDGF inhibitor as a targeted therapy for PAH patients.
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Progression of pulmonary hypertension is associated with increased proliferation and migration of pulmonary vascular smooth muscle cells. PDGF is a potent mitogen and involved in this process. We now report that the PDGF receptor antagonist STI571 (imatinib) reversed advanced pulmonary vascular disease in 2 animal models of pulmonary hypertension. ⋯ Moreover, expression of the PDGF receptor was found to be significantly increased in lung tissue from pulmonary arterial hypertension patients compared with healthy donor lung tissue. We conclude that STI571 reverses vascular remodeling and cor pulmonale in severe experimental pulmonary hypertension regardless of the initiating stimulus. This regimen offers a unique novel approach for antire-modeling therapy in progressed pulmonary hypertension.
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Cold hyperalgesia is a well-documented symptom of inflammatory and neuropathic pain; however, the underlying mechanisms of this enhanced sensitivity to cold are poorly understood. A subset of transient receptor potential (TRP) channels mediates thermosensation and is expressed in sensory tissues, such as nociceptors and skin. Here we report that the pharmacological blockade of TRPA1 in primary sensory neurons reversed cold hyperalgesia caused by inflammation and nerve injury. ⋯ Conversely, intrathecal injection of NGF, but not glial cell line-derived neurotrophic factor, increased TRPA1 in DRG neurons through the p38 MAPK pathway. Together, these results demonstrate that an NGF-induced TRPA1 increase in sensory neurons via p38 activation is necessary for cold hyperalgesia. Thus, blocking TRPA1 in sensory neurons might provide a fruitful strategy for treating cold hyperalgesia caused by inflammation and nerve damage.
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Amyloid beta-peptide (Abeta) appears to play a key pathogenic role in Alzheimer disease (AD). Immune therapy in mouse models of AD via Abeta immunization or passive administration of Abeta antibodies markedly reduces Abeta levels and reverses behavioral impairment. However, a human trial of Abeta immunization led to meningoencephalitis in some patients and was discontinued. ⋯ Vaccinated animals developed activated microglia that colocalized with Abeta fibrils, and the extent of microglial activation correlated strongly with the decrease in Abeta fibrils. Activation of microglia and clearing of Abeta occurred with the adjuvant alone, although to a lesser degree. Our results identify a novel approach to immune therapy for AD that involves clearing of Abeta through the utilization of compounds that have been safely tested on or are currently in use in humans.
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Randomized Controlled Trial Clinical Trial
Intensive insulin therapy protects the endothelium of critically ill patients.
The vascular endothelium controls vasomotor tone and microvascular flow and regulates trafficking of nutrients and biologically active molecules. When endothelial activation is excessive, compromised microcirculation and subsequent cellular hypoxia contribute to the risk of organ failure. We hypothesized that strict blood glucose control with insulin during critical illness protects the endothelium, mediating prevention of organ failure and death. ⋯ In contrast, prevention of hyperglycemia by intensive insulin therapy suppressed iNOS gene expression in postmortem liver and skeletal muscle, possibly in part via reduced NF-kappaB activation, and lowered the elevated circulating NO levels in both survivors and nonsurvivors. These effects on the endothelium statistically explained a significant part of the improved patient outcome with intensive insulin therapy. In conclusion, maintaining normoglycemia with intensive insulin therapy during critical illness protects the endothelium, likely in part via inhibition of excessive iNOS-induced NO release, and thereby contributes to prevention of organ failure and death.