Lung Impedance Measurements Using Tracked Breathing

The forced Oscillation Technique (FOT) can be used to measure lung impedance continuously during breathing. However, spectral overlap between the breathing waveform and the applied flow oscillation can be problematic if the frequency content of spontaneous breathing is unknown. This problem motivated us to develop a modification to the FOT system called the Tracked Breathing Trainer. The modification uses biofeedback to constrain subjects to breathe at a single predetermined frequency. This thesis investigates the engineering and physiological aspects of the modification we made. We studied 8 adult non-asthmatic and 8 adult asthmatic subjects. Three 16 s perturbatory flow oscillation signals ranging from 1-40 Hz were used on the subjects. Each subject received three trials per perturbation for both spontaneous and tracked breathing. We then fitted a resistance-elastance-inertance model of the lung to each data set. For non-asthmatic subjects, the average resistance (R) and elastance (E) values for the first spontaneous breathing trial were 2.5±0.15 cmH2O.s.ml-1 and 18.1±3.55 cmH2O.ml-1, and for the third spontaneous breathing trial were 2.4±0.12 cmH2O.s.ml-1 and 21.8±4 cmH2O.ml-1. R and E for the first tracked breathing trial were 2.3±0.21 cmH2O.s.ml-1 and 33.6±7.4 cmH2O.ml-1, and for the third tracked breathing trial were 2.4±0.14 cmH2O.s.ml-1 and 25.75±4.3 cmH2O.ml-1, respectively. For asthmatic subjects, the average R and E values for the first spontaneous breathing trial were 3.32±0.68 cmH2O.s.ml-1 and 39.13±9.8 cmH2O.ml-1, and for the third spontaneous breathing trial were 3.12±0.15 cmH2O.s.ml-1 and 39.91±6.2 cmH2O.ml-1. R and E for the first tracked breathing trial were 2.86±0.15 cmH2O.s.ml-1 and 32.47±4.1 cmH2O.ml-1, and for the third tracked breathing trial were 2.86±0.21 cmH2O.s.ml-1 and 33.89±10 cmH2O.ml-1, respectively. These results show that R was consistently lower during tracked breathing than spontaneous breathing in both non-asthmatic and asthmatic subjects. However, an increase in E was observed during tracked breathing. We suspect this effect may have resulted from dynamic hyperinflation. These results also show that R and E are reproducible with both spontaneous and tracked breathing, and that R and E were not noticeably different between both breathing maneuvers. We conclude that using biofeedback to control the breathing pattern during application of the FOT in normal subjects does not significantly affect impedance measurements, and thus may be useful for avoiding spectral overlap between FOT perturbations and the breathing pattern

Novel Device for Measuring Lung Function using Oscillometry

The forced oscillation technique (FOT) is a non-invasive means of measuring lung mechanics. Broad-band oscillations in flow are delivered to the lungs while the resultant pressure oscillations are recorded. These signals are processed to yield the input impedance of the respiratory system (Zrs), which encapsulates the mechanical properties of the lung over the frequency range spanned by the oscillations. Clinically, can be used to assess pulmonary pathologies such as asthma and COPD. Standard methods of performing FOT are limited to the non-ambulatory clinical setting. Production of a light-weight device that operates without an external power source would allow real-time measurements of in a wide variety of more natural settings. Breath-driven oscillators, such as the Smith’s Medical Acapella and D R Burton vPEP, are currently used clinically to help cystic fibrosis patients clear mucus from their lungs by generating pressure oscillations that travel into the airways. We hypothesized that these oscillations could be used to determine . We performed FOT on healthy individuals without history of lung disease using a calibrated piston oscillator (Flexivent) to determine reference between 1 and 20 Hz. We then measured airway pressure and flow using the same sensors but with the oscillations produced by the Acapella and vPEP during tidal breathing. Respiratory resistance (Rrs), elastance (Ers) and Inertance (Irs) were determined by fitting the single-compartment model of the respiratory system to the time-domain signals from all three measurement devices. Correlation coefficients, Bland-Altman plots, and coefficients of variation were used to compare the results obtained with the three devices. We found bias values of 0.633857 [0.214382378, 1.053331908] cmH2O.s.L-1, 0.041333 [-0.38432604, 0.46699271] cmH2O.s.L-1 for comparing the Flexivent against the Acapella and vPEP, respectively. Coefficients of variation of 9.003%, 9.855%, and 9.643% were obtained for the Flexivent, Acapella, and vPEP, respectively. These results demonstrate that breath-driven oscillators are promising alternatives to conventional powered oscillators for the measurement of

Obesity exacerbates influenza-induced respiratory disease via the arachidonic acid-p38 MAPK pathway

Obesity is a risk factor for severe influenza, and asthma exacerbations caused by respiratory viral infections. We investigated mechanisms that increase the severity of airway disease related to influenza in obesity using cells derived from obese and lean individuals, and in vitro and in vivo models. Primary human nasal epithelial cells (pHNECs) derived from obese compared with lean individuals developed increased inflammation and injury in response to influenza A virus (IAV). Obese mice infected with influenza developed increased airway inflammation, lung injury and elastance, but had a decreased interferon response, compared with lean mice. Lung arachidonic acid (AA) levels increased in obese mice infected with IAV; arachidonic acid increased inflammatory cytokines and injury markers in response to IAV in human bronchial epithelial (HBE) cells. Obesity in mice, and AA in HBE cells, increased activation of p38 MAPK signaling following IAV infection; inhibiting this pathway attenuated inflammation, injury and tissue elastance responses, and improved survival. In summary, obesity increases disease severity in response to influenza infection through activation of the p38 MAPK pathway in response to altered arachidonic acid signaling

Oxidation-Dependent Activation of Src Kinase Mediates Epithelial IL-33 Production and Signaling during Acute Airway Allergen Challenge

The respiratory epithelium forms the first line of defense against inhaled pathogens, and acts as an important source of innate cytokine responses to environmental insults. One critical mediator of these responses is the IL-1 family cytokine, IL-33, which is rapidly secreted upon acute epithelial injury as an alarmin and induces type 2 immune responses. Our recent work highlighted the importance of the NADPH oxidase dual oxidase 1 (DUOX1) in acute airway epithelial IL-33 secretion by various airborne allergens, associated with H(2)O(2) production and redox-dependent activation of Src kinases and epidermal growth factor receptor (EGFR) signaling. Here, we show that IL-33 secretion in response to acute airway challenge with house dust mite (HDM) allergen critically depends on the activation of Src by a DUOX1-dependent oxidative mechanism. Intriguingly, HDM-induced epithelial IL-33 secretion was dramatically attenuated by siRNA- or antibody-based approaches to block IL-33 signaling through its receptor IL1RL1(ST2), indicating that HDM-induced IL-33 secretion includes a positive feed-forward mechanism involving ST2-dependent IL-33 signaling. Moreover, activation of type 2 cytokine responses by direct airway IL-33 administration was associated with ST2-dependent activation of DUOX1-mediated H(2)O(2) production and redox-based activation of Src and EGFR, and was attenuated in Duox1(−/−) and Src(+/−) mice, indicating that IL-33-induced epithelial signaling and subsequent airway responses involve DUOX1/Src-dependent pathways. Collectively, our findings suggest an intricate relationship between DUOX1, Src and IL-33 signaling in the activation of innate type 2 immune responses to allergens, involving DUOX1-dependent epithelial Src/EGFR activation in initial IL-33 secretion and in subsequent IL-33 signaling through ST2 activation

Protein disulfide isomerase–endoplasmic reticulum resident protein 57 regulates allergen-induced airways inflammation, fibrosis, and hyperresponsiveness

BackgroundEvidence for association between asthma and the unfolded protein response is emerging. Endoplasmic reticulum resident protein 57 (ERp57) is an endoplasmic reticulum-localized redox chaperone involved in folding and secretion of glycoproteins. We have previously demonstrated that ERp57 is upregulated in allergen-challenged human and murine lung epithelial cells. However, the role of ERp57 in asthma pathophysiology is unknown.ObjectivesHere we sought to examine the contribution of airway epithelium-specific ERp57 in the pathogenesis of allergic asthma.MethodsWe examined the expression of ERp57 in human asthmatic airway epithelium and used murine models of allergic asthma to evaluate the relevance of epithelium-specific ERp57.ResultsLung biopsy specimens from asthmatic and nonasthmatic patients revealed a predominant increase in ERp57 levels in epithelium of asthmatic patients. Deletion of ERp57 resulted in a significant decrease in inflammatory cell counts and airways resistance in a murine model of allergic asthma. Furthermore, we observed that disulfide bridges in eotaxin, epidermal growth factor, and periostin were also decreased in the lungs of house dust mite-challenged ERp57-deleted mice. Fibrotic markers, such as collagen and α smooth muscle actin, were also significantly decreased in the lungs of ERp57-deleted mice. Furthermore, adaptive immune responses were dispensable for house dust mite-induced endoplasmic reticulum stress and airways fibrosis.ConclusionsHere we show that ERp57 levels are increased in the airway epithelium of asthmatic patients and in mice with allergic airways disease. The ERp57 level increase is associated with redox modification of proinflammatory, apoptotic, and fibrotic mediators and contributes to airways hyperresponsiveness. The strategies to inhibit ERp57 specifically within the airways epithelium might provide an opportunity to alleviate the allergic asthma phenotype

Downregulation of DUOX1 function contributes to aging-related impairment of innate airway injury responses and accelerated senile emphysema

Aging is associated with a gradual loss of lung function due to increased cellular senescence, decreased regenerative capacity, and impaired innate host defense. One important aspect of innate airway epithelial host defense to nonmicrobial triggers is the secretion of alarmins such as IL-33 and activation of type 2 inflammation, which were previously found to depend on activation of the NADPH oxidase (NOX) homolog DUOX1, and redox-dependent signaling pathways that promote alarmin secretion. Here, we demonstrate that normal aging of C57BL/6J mice resulted in markedly decreased lung innate epithelial type 2 responses to exogenous triggers such as the airborne allergen Dermatophagoides pteronyssinus, which was associated with marked downregulation of DUOX1, as well as DUOX1-mediated redox-dependent signaling. DUOX1 deficiency was also found to accelerate age-related airspace enlargement and decline in lung function but did not consistently affect other features of lung aging such as senescence-associated inflammation. Intriguingly, observations of age-related DUOX1 downregulation and enhanced airspace enlargement due to DUOX1 deficiency in C57BL/6J mice, which lack a functional mitochondrial nicotinamide nucleotide transhydrogenase (NNT), were much less dramatic in C57BL/6NJ mice with normal NNT function, although the latter mice also displayed impaired innate epithelial injury responses with advancing age. Overall, our findings indicate a marked aging-dependent decline in (DUOX1-dependent) innate airway injury responses to external nonmicrobial triggers, but the impact of aging on DUOX1 downregulation and its significance for age-related senile emphysema development was variable between different C57BL6 substrains, possibly related to metabolic alterations due to differences in NNT function