Biology subjects

Pavelkova, N.

Publications and source records attributed to Pavelkova, N..

2 recordsLinked to original sources

bioRxiv2025

Anatomical and functional mapping of vagal nociceptive sensory nerve subsets innervating the mouse lower airways by intersectional genetics

Most vagal sensory afferents innervating the lower airways are activated by noxious stimuli including irritants (e.g. TRPV1 agonist capsaicin) and inflammatory mediators, causing nociceptive cardiorespiratory reflexes (e.g. cough, bronchospasm, changes in respiratory drive and heart rate). Vagal ganglia are comprised of embryologically distinct nodose and jugular neurons, but little is known of their specific contribution to nociceptive reflexes. Using a novel TRPV1Flp mouse in combination with P2X2Cre, Tac1Cre, intersectional reporter mice and AAV we mapped and modulated distinct nociceptive afferents. TRPV1+P2X2+ neurons were found exclusively in the nodose ganglion and were activated by {beta}mATP and capsaicin but rarely expressed Tac1. TRPV1+P2X2+ fibers innervated the lungs (many projected into the alveoli) but not the trachea. Centrally they innervated the nucleus tractus solitarius (nTS). >90% of TRPV1+Tac1+ neurons were found in the jugular ganglion and were activated by capsaicin but not {beta}mATP. TRPV1+Tac1+ fibers innervated the lungs (although none projected into the alveoli) and the trachea submucosa. They terminated solely in the paratrigeminal complex (Pa5). Many TRPV1-Tac1+ neurons were found in both nodose and jugular ganglia that innervated the trachea and large pulmonary airways. These projected to both nTS and Pa5. Using intersectional chemogenetics we selectively stimulated lower airway afferent subsets using intravenous injections of clozapine-N-oxide (CNO). Activation of TRPV1+, TRPV1+P2X2+ or TRPV1+Tac1+ fibers evoked bradycardia and bradypnea. Activation of Tac1+ fibers evoked tachycardia and tachypnea. Activation of vagal TRPV1-Tac1+ neurons only evoked tachycardia. These data show the distinct innervation patterns and reflex function of multiple nociceptive vagal afferent subsets.

physiology↗

bioRxiv2024

Pulmonary Fibrosis Ferret Model Demonstrates Sustained Fibrosis, Restrictive Physiology, and Aberrant Repair

RationaleThe role of MUC5B mucin expression in IPF pathogenesis is unknown. Bleomycin-exposed rodent models do not exhibit sustained fibrosis or airway remodeling. Unlike mice, ferrets have human-like distribution of MUC5B expressing cell types and natively express the risk-conferring variant that induces high MUC5B expression in humans. We hypothesized that ferrets would consequently exhibit aberrant repair to propagate fibrosis similar to human IPF. MethodsBleomycin (5U/kg) or saline-control was micro-sprayed intratracheally then wild-type ferrets were evaluated through 22 wks. Clinical phenotype was assessed with lung function. Fibrosis was assessed with {micro}CT imaging and comparative histology with Ashcroft scoring. Airway remodeling was assessed with histology and quantitative immunofluorescence. ResultsBleomycin ferrets exhibited sustained restrictive physiology including decreased inspiratory capacity, decreased compliance, and shifted Pressure-Volume loops through 22 wks. Volumetric {micro}CT analysis revealed increased opacification of the lung bleomycin-ferrets. Histology showed extensive fibrotic injury that matured over time and MUC5B-positive cystic structures in the distal lung suggestive of honeycombing. Bleomycin ferrets had increased proportion of small airways that were double-positive for CCSP and alpha-tubulin compared to controls, indicating an aberrant proximalization repair phenotype. Notably, this aberrant repair was associated with extent of fibrotic injury at the airway level. ConclusionsBleomycin-exposed ferrets exhibit sustained fibrosis through 22 wks and have pathologic features of IPF not found in rodents. Ferrets exhibited proximalization of the distal airways and other pathologic features characteristic of human IPF. MUC5B expression through native cell types may play a key role in promoting airway remodeling and lung injury in IPF.

physiology↗