Nicolle J. Domnik

Recent advances and contraversies on the role of pulmonary neuroepithelial bodies as airway sensors.

Pulmonary neuroepithelial bodies are polymodal sensors widely distributed within the airway mucosa of mammals and other species. Neuroepithelial body cells store and most likely release serotonin and peptides as transmitters. Neuroepithelial bodies have a complex innervation that includes vagal sensory afferent fibers and dorsal root ganglion fibers. Neuroepithelial body cells respond to a number of intraluminal airway stimuli, including hypoxia, hypercarbia, and mechanical stretch. This article reviews recent findings in the cellular and molecular biology of neuroepithelial body cells and their potential role as airway sensors involved in the control of respiration, particularly during the perinatal period. Alternate hypotheses and areas of controversy regarding potential function as mechanosensory receptors involved in pulmonary reflexes are discussed.

Pulmonary neuroepithelial bodies as airway sensors: putative role in the generation of dyspnea.

The neuroepithelial bodies (NEB) of the intrapulmonary airways (AW) are multimodal AW sensors responding to a variety of stimuli including hypoxia, hypercarbia, and mechanical stretch. NEBs are richly innervated by a diverse population of mostly vagal afferent nerve fibers and owing to their early developmental maturation may be especially important during the perinatal period. This article reviews recent findings of NEB functional morphology and innervation, and postulates a role in the generation of dyspnea. This is based on their potential for transduction of dyspneic stimuli and findings of NEB cell abnormalities in a number of pulmonary disorders presenting with this symptom.

OVA-induced airway hyperresponsiveness alters murine heart rate variability and body temperature

Altered autonomic (ANS) tone in chronic respiratory disease is implicated as a factor in cardiovascular co-morbidities, yet no studies address its impact on cardiovascular function in the presence of murine allergic airway (AW) hyperresponsiveness (AHR). Since antigen (Ag)-induced AHR is used to model allergic asthma (in which ANS alterations have been reported), we performed a pilot study to assess measurement feasibility of, as well as the impact of allergic sensitization to ovalbumin (OVA) on, heart rate variability (HRV) in a murine model. Heart rate (HR), body temperature (TB), and time- and frequency-domain HRV analyses, a reflection of ANS control, were obtained in chronically instrumented mice (telemetry) before, during and for 22 h after OVA or saline aerosolization in sensitized (OVA) or Alum adjuvant control exposed animals. OVA mice diverged significantly from Alum mice with respect to change in HR during aerosol challenge (P < 0.001, Two-Way ANOVA; HR max change Ctrl = +80 ± 10 bpm vs. OVA = +1 ± 23 bpm, mean ± SEM), and displayed elevated HR during the subsequent dark cycle (P = 0.006). Sensitization decreased the TB during aerosol challenge (P < 0.001). Sensitized mice had decreased HRV prior to challenge (SDNN: P = 0.038; Low frequency (LF) power: P = 0.021; Low/high Frequency (HF) power: P = 0.042), and increased HRV during Ag challenge (RMSSD: P = 0.047; pNN6: P = 0.039). Sensitized mice displayed decreased HRV subsequent to OVA challenge, primarily in the dark cycle (RMSSD: P = 0.018; pNN6: P ≤ 0.001; LF: P ≤ 0.001; HF: P = 0.040; LF/HF: P ≤ 0.001). We conclude that implanted telemetry technology is an effective method to assess the ANS impact of allergic sensitization. Preliminary results show mild sensitization is associated with reduced HRV and a suppression of the acute TB-response to OVA challenge. This approach to assess altered ANS control in the acute OVA model may also be beneficial in chronic AHR models.

Acute bronchodilator therapy does not reduce wasted ventilation during exercise in COPD

This randomized, double-blind, crossover study aimed to determine if acute treatment with inhaled bronchodilators, by improving regional lung hyperinflation and ventilation distribution, would reduce dead space-to-tidal volume ratio (VD/VT); thus contributing to improved exertional dyspnea in COPD. Twenty COPD patients (FEV1 = 50 ± 15% predicted; mean ± SD) performed pulmonary function tests and symptom-limited constant-work rate exercise at 75% peak-work rate (with arterialized capillary blood gases) after nebulized bronchodilator (BD; ipratropium 0.5mg + salbutamol 2.5 mg) or placebo (PL; normal saline). After BD versus PL: Functional residual capacity decreased by 0.4L (p = .0001). Isotime during exercise after BD versus PL (p < .05): dyspnea decreased: 1.2 ± 1.9 Borg-units; minute ventilation increased: 3.8 ± 5.5 L/min; IC increased: 0.24 ± 0.28 L and VT increased 0.19 ± 0.16 L. There was no significant difference in arterial CO2 tension or VD/VT, but alveolar ventilation increased by 3.8 ± 5.5 L/min (p = .02). Post-BD improvements in respiratory mechanics explained 51% of dyspnea reduction at a standardized exercise time. Bronchodilator-induced improvements in respiratory mechanics were not associated with reduced wasted ventilation - a residual contributory factor to exertional dyspnea during exercise in COPD.

Automated Non-invasive Video-Microscopy of Oyster Spat Heart Rate during Acute Temperature Change: Impact of Acclimation Temperature

We developed an automated, non-invasive method to detect real-time cardiac contraction in post-larval (1.1–1.7 mm length), juvenile oysters (i.e., oyster spat) via a fiber-optic trans-illumination system. The system is housed within a temperature-controlled chamber and video microscopy imaging of the heart was coupled with video edge-detection to measure cardiac contraction, inter-beat interval, and heart rate (HR). We used the method to address the hypothesis that cool acclimation (10°C vs. 22°C—Ta10 or Ta22, respectively; each n = 8) would preserve cardiac phenotype (assessed via HR variability, HRV analysis and maintained cardiac activity) during acute temperature changes. The temperature ramp (TR) protocol comprised 2°C steps (10 min/experimental temperature, Texp) from 22°C to 10°C to 22°C. HR was related to Texp in both acclimation groups. Spat became asystolic at low temperatures, particularly Ta22 spat (Ta22: 8/8 vs. Ta10: 3/8 asystolic at Texp = 10°C). The rate of HR decrease during cooling was less in Ta10 vs. Ta22 spat when asystole was included in analysis (P = 0.026). Time-domain HRV was inversely related to temperature and elevated in Ta10 vs. Ta22 spat (P < 0.001), whereas a lack of defined peaks in spectral density precluded frequency-domain analysis. Application of the method during an acute cooling challenge revealed that cool temperature acclimation preserved active cardiac contraction in oyster spat and increased time-domain HRV responses, whereas warm acclimation enhanced asystole. These physiologic changes highlight the need for studies of mechanisms, and have translational potential for oyster aquaculture practices.

Development of the Innervation of the Lower Airways: Structure and Function

This chapter explores the development, structure, and function of the lower airways. Sections 1 and 2 describe the anatomy, morphology, and distribution of the pulmonary innervation in pre- and postnatal murine, porcine, and human lungs. Recent advances in techniques (e.g., confocal microscopy, optical projection tomography) are reviewed with respect to their use in mutant/transgenic models, which have increased our understanding of pulmonary innervation throughout the pseudoglandular, canalicular, and saccular stages of development. Significant advances in our understanding of the potential role of the neuroendocrine cell system, including neuroepithelial bodies, are examined with respect to the origins of chemo- and mechano-sensation in the lung and the impact on airway regulation. Section 3 addresses pre- and postnatal airway smooth muscle function, while Section 4 provides an overview of the role of muscarinic receptors in the lung. In summary, this chapter documents the innervation of the lung and airway smooth muscle throughout development.Abstract This chapter explores the development, structure, and function of the lower airways. Sections 1 and 2 describe the anatomy, morphology, and distribution of the pulmonary innervation in pre- and postnatal murine, porcine, and human lungs. Recent advances in techniques (e.g., confocal microscopy, optical projection tomography) are reviewed with respect to their use in mutant/transgenic models, which have increased our understanding of pulmonary innervation throughout the pseudoglandular, canalicular, and saccular stages of development. Significant advances in our understanding of the potential role of the neuroendocrine cell system, including neuroepithelial bodies, are examined with respect to the origins of chemo- and mechano-sensation in the lung and the impact on airway regulation. Section 3 addresses pre- and postnatal airway smooth muscle function, while Section 4 provides an overview of the role of muscarinic receptors in the lung. In summary, this chapter documents the innervation of the lung and airway smooth muscle throughout development.