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Pellegrino, P. R.

Publications and source records attributed to Pellegrino, P. R..

3 recordsLinked to original sources
bioRxiv2025

Neural Inflammation in Thoracic Dorsal Root Ganglia Mediates Cardiopulmonary Spinal Afferent Sensitization in Chronic Heart Failure

The cardiac sympathetic afferent reflex (CSAR) and pulmonary spinal afferent reflex (PSAR) amplify sympathetic outflow, and their sensitization contributes to chronic heart failure (CHF). Using a myocardial infarction (MI) rat model, molecular profiling, imaging, and functional assays revealed that thoracic dorsal root ganglia (DRGs) undergo marked macrophage and glial activation and suppression of voltage-gated potassium (Kv) channels after MI. In vitro studies confirmed that pro-inflammatory cytokines and activated macrophages directly reduce Kv channel expression and activity in DRG neurons. Cardiac afferents mediated cytokine transport from the heart to DRGs, driving macrophage infiltration in a cytokine receptor-dependent manner. Anti-inflammatory strategies including systemic minocycline, liposomal clodronate-induced macrophage depletion, or local epidural dexamethasone prodrug delivery reduced neuroinflammation, restored Kv channel levels, attenuated the exaggerated CSAR and PSAR, and improved cardiac remodeling. These findings highlight a cytokine uptake-driven inflammatory pathway in cardiopulmonary spinal afferent sensitization and support targeted DRG anti-inflammatory therapy as a potential cardioprotective approach. AbstractThe cardiac sympathetic afferent reflex (CSAR) and pulmonary spinal afferent reflex (PSAR) amplify sympathetic activity and may contribute to chronic heart failure (CHF). We hypothesized that neural inflammation in thoracic dorsal root ganglia (DRGs) drives cardiopulmonary afferent sensitization through suppression of voltage-gated potassium (Kv) channels after myocardial infarction (MI). MI was induced in rats by coronary ligation. Molecular profiling, immunofluorescence, tissue clearing, and functional assays were used to assess neuroinflammation and reflex responses. Post-MI, thoracic DRGs showed macrophage infiltration, glial activation, cytokine upregulation, and reduced Kv channel expression. Bulk RNA-seq identified enrichment of macrophage activation-related genes, and in vitro studies confirmed that pro-inflammatory cytokines and activated macrophages suppressed Kv channels and increased DRG neuron excitability. Epicardial injection of biotinylated TNF- demonstrated cardiac afferent-mediated cytokine transport to DRGs, inducing macrophage infiltration via a cytokine receptor-dependent mechanism. Anti-inflammatory interventions including oral minocycline, systemic macrophage depletion, and local epidural delivery of thermo-responsive hydrogel-forming dexamethasone prodrug (ProGel-Dex) significantly reduced DRG neuroinflammation, restored Kv channel levels, and attenuated exaggerated CSAR and PSAR responses. ProGel-Dex also improved cardiac chamber dilation in the post-MI rats. These findings identify a cytokine uptake-glial activation- macrophage activation pathway as a driver of cardiopulmonary afferent sensitization after MI. Targeting DRG inflammation, particularly with sustained local dexamethasone delivery using ProGel-Dex, offers a precision medicine to dampen pathological sympathetic activation and improve cardiac outcomes in CHF. HighlightsO_LIBoth cardiac (CSAR) and pulmonary (PSAR) spinal afferent reflexes are sensitized after myocardial infarction, contributing to sympathetic overactivation. C_LIO_LIThoracic dorsal root ganglia (T1-T4) exhibit macrophage activation, glial responses, pro- inflammatory cytokine upregulation, and suppression of Kv channels following MI. C_LIO_LICardiac afferents mediate receptor-dependent uptake and transport of cytokines (e.g., TNF-) from the heart to DRGs, driving macrophage infiltration and inflammation. C_LIO_LIActivated macrophages and pro-inflammatory cytokines reduce Kv channel expression and Kv current density (Ito) in DRG neurons, enhancing excitability. C_LIO_LIAnti-inflammatory strategies including minocycline, liposomal clodronate-induced macrophage depletion, and local epidural dexamethasone prodrug attenuate neuroinflammation, restore Kv channel expression, and suppress exaggerated CSAR/PSAR. C_LIO_LITargeting DRG inflammation, particularly via sustained epidural dexamethasone delivery, represents a promising cardioprotective precise medicine. C_LI

neuroscience↗
bioRxiv2025

Sympathetic vasomotion as an early marker of hemorrhage

Each year, over 1.8 million people die from hemorrhagic shock, and, since the median time from onset to death is only two hours, early recognition is the cornerstone of management. The sympathetic nervous system is the fastest physiological hemodynamic compensatory mechanism, and we have developed a novel measure of sympathetic vascular control called sympathetic vasomotion which could serve as an early marker of hemorrhage. We performed unilateral renal denervation on six rabbits and instrumented these rabbits with bilateral renal flow probes and arterial pressure telemeters to allow for measurement of sympathetic vasomotion in paired vascular beds that differed only by sympathetic innervation. After a two-week recovery period, conscious rabbits then underwent controlled blood withdrawal via an auricular arterial catheter to simulate hemorrhage. Vasomotion differences between innervated and denervated kidneys in admittance gain, phase shift, and coherence increased significantly prior to increases in heart rate or decreases in blood pressure. These data suggest that sympathetic vasomotion could be a useful physiologically based biomarker for the early detection of hemorrhage. Further studies are needed to evaluate the utility of monitoring the sympathetic nervous system in clinical settings. NEW & NOTEWORTHYSympathetic vasomotion, a novel marker of sympathetic outflow, increases prior to other hemodynamic changes. Sympathetic vasomotion could serve as an early detection tool for hemorrhage that facilitates prompt and precise resuscitation.

physiology↗
bioRxiv2025

Sympathetic Vasomotion Reflects Catheter-based Radiofrequency Renal Denervation

The field of renal denervation remains challenged by the inability to confirm successful ablation of the targeted renal sympathetic nerves. The availability of technology to measure regional blood flow in real time makes sympathetic control of the renal vasculature a logical endpoint to assess effective renal denervation, but autoregulatory mechanisms mask effects on mean renal blood flow. We hypothesized that renal sympathetic vasomotion, a novel marker of rhythmic sympathetic control, reflects successive rounds of catheter-based radiofrequency renal denervation. To test this, ten pigs underwent unilateral surgical renal denervation, recovered for at least seven days, and then underwent four successive rounds of catheter-based radiofrequency denervation of the contralateral kidney. Bilateral renal blood flow velocity and abdominal aortic pressure were measured before and after ablations to assess renal vasomotion. Prior to catheter-based denervation, the renal vasomotion profiles of the innervated and surgically denervated kidneys differed significantly (P < 0.005). Ablation of the largest renal branch artery reduced renal sympathetic vasomotion by 52%. Ablation of the remaining renal branch arteries reduced sympathetic vasomotion 95% from baseline and eliminated the statistical differences between surgically and catheter denervated kidneys. Two additional rounds of catheter denervation of the main renal artery did not consistently decrease renal sympathetic vasomotion magnitude any further. These results indicate that renal sympathetic vasomotion could provide intraprocedural feedback for interventionalists performing catheter-based renal denervation and thereby improve the efficacy, safety, and consistency of this antihypertensive intervention.

physiology↗