VIP/PACAP Signaling as an Alternative Target During Hyperoxic Exposure in Preterm Newborns

The use of oxygen therapy (high doses of oxygen - hyperoxia) in the treatment of premature infants results in their survival. However, it also results in a high incidence of chronic lung disease known as bronchopulmonary dysplasia, a disease in which airway hyper-responsiveness and pulmonary hypertension are well known as consequences. In our previous studies, we have shown that hyperoxia causes airway hyper-reactivity, characterized by an increased constrictive and impaired airway smooth muscle relaxation due to a reduced release of relaxant molecules such as nitric oxide, measured under in vivo and in vitro conditions (extra- and intrapulmonary) airways. In addition, the relaxation pathway of the vasoactive intestinal peptide (VIP) and/or pituitary adenylate cyclase activating peptide (PACAP) is another part of this system that plays an important role in the airway caliber. Peptide, which activates VIP cyclase and pituitary adenylate cyclase, has prolonged airway smooth muscle activity. It has long been known that VIP inhibits airway smooth muscle cell proliferation in a mouse model of asthma, but there is no data about its role in the regulation of airway and tracheal smooth muscle contractility during hyperoxic exposure of preterm newborns.

4D Computed Tomography for Dynamic Upper Airway Evaluation in Robin Sequence

Thorough assessment of dynamic upper airway obstruction (UAO) in Robin sequence (RS) is critical, but traditional evaluation modalities have significant limitations. Four-dimensional computed tomography (4D-CT) is promising in that it enables objective and quantitative evaluation throughout all phases of respiration. However, there exist few protocols or analysis tools to assist in obtaining and interpreting the vast amounts of obtained data. A protocol and set of data analysis tools were developed to enable quantification and visualization of dynamic 4D-CT data. This methodology was applied to a sample case at 2 time points. In the patient with RS, overall increases in normalized airway caliber were observed from 5 weeks to 1 year. There was, however, continued dynamic obstruction at all airway levels, though objective measures of UAO did improve at the nasopharynx and oropharynx. Use of 4D-CT and novel analyses provide additional quantitative information to evaluate UAO in patients with RS.

Asthma in elderly is characterized by increased sputum neutrophils, lower airway caliber variability and air trapping

Background Elderly asthmatics represent an important group that is often excluded from clinical studies. In this study we wanted to present characteristics of asthmatics older than 70 years old as compared to younger patients. Methods We conducted a retrospective analysis on a series of 758 asthmatics subdivided in three groups: lower than 40, between 40 and 70 and older than 70. All the patients who had a successful sputum induction were included in the study. Results Older patients had a higher Body Mass Index, had less active smokers and were more often treated with Long Acting anti-Muscarinic Agents. We found a significant increase in sputum neutrophil counts with ageing. There was no significant difference in blood inflammatory cell counts whatever the age group. Forced expiratory volume in one second (FEV1) and FEV1/FVC values were significantly lower in elderly who had lower bronchial hyperresponsiveness and signs of air trapping. We found a lower occurrence of the allergic component in advanced ages. Asthmatics older than 70 years old had later onset of the disease and a significant longer disease duration. Conclusion Our study highlights that asthmatics older than 70 years old have higher bronchial neutrophilic inflammation, a poorer lung function, signs of air trapping and lower airway variability. The role of immunosenescence inducing chronic low-grade inflammation in this asthma subtype remains to be elucidated.

0164 Evidence Suggesting Early Airway Collapse as Cause of Spontaneous Arousals

Introduction Spontaneous arousals can occur in response to a number of stimuli like noise, movement, hypoxia, or airway obstruction. Some arousals occur “spontaneously” and in individuals donning a hyper-arousable phenotype, spontaneous arousals can dominate the sleep architecture. While arousal mechanisms for some stimuli have been well described, there is a profound lack of knowledge to explain spontaneous arousals. During clinical testing of a device that was designed by SleepMethods, Inc. to anticipate obstructive sleep apnea events by the ability to sense minute airway caliber changes, it was noted, incidentally that the device would signal impeding airway collapse but a spontaneous arousal followed the signal before an obstructive airway event ever developed. This phenomenon was observed many times within and between subjects, suggesting the possibility that very early airway changes are causing “spontaneous arousals” Methods Ten adults (7M;3F) aged 18-80y/o (avg. 54.7y/o) with a known AHI ≥ 15/hr (avg. AHI = 42.6/hr) underwent 1 overnight PSG recording while wearing the device. Patients were required to forego their usual CPAP therapy on the night of study in efforts to expose the device to an adequate number of total obstructive events (defined as apneas and hypopneas; RERAs and snores were excluded). Standard PSG analysis was performed. Scoring rules were applied to determine whether signals were true/false positives and/or true/false negatives based on pre-clinical data showing anticipation accuracy for up to 45 seconds prior to an obstructive airway event. Signals designed to herald obstructive events were noted, incidentally, appearing prior to spontaneous arousals. Results Preliminary results suggest that early phases of airway collapse, as the airway progresses from patency to clinically significant obstruction, are causing EEG arousals which, by current standards, are considered “spontaneous”. Because these findings were incidental to another primary purpose of the clinical study, data analysis is in early stages but currently suggesting at least an associative relationship. Conclusion If final data analysis shows statistically significant correlation between early airway collapse and “spontaneous arousals”, it may have tremendous implications for patients with hyper-arousability, insomnia, and/or pathologically elevated spontaneous arousal indices by proposing therapies aimed at airway patency maintenance. Support N/A

Microscale to mesoscale analysis of parenchymal tethering: the effect of heterogeneous alveolar pressures on the pulmonary mechanics of compliant airways

In the healthy lung, bronchi are tethered open by the surrounding parenchyma; for a uniform distribution of these peribronchial structures, the solution is well known. An open question remains regarding the effect of a distributed set of collapsed alveoli, as can occur in disease. Here, we address this question by developing and analyzing microscale finite-element models of systems of heterogeneously inflated alveoli to determine the range and extent of parenchymal tethering effects on a neighboring collapsible airway. This analysis demonstrates that micromechanical stresses extend over a range of ∼5 airway radii, and this behavior is dictated primarily by the fraction, not distribution, of collapsed alveoli in that region. A mesoscale analysis of the microscale data identifies an effective shear modulus, Geff, that accurately characterizes the parenchymal support as a function of the average transpulmonary pressure of the surrounding alveoli. We demonstrate the use of this formulation by analyzing a simple model of a single collapsible airway surrounded by heterogeneously inflated alveoli (a “pig-in-a-blanket” model), which quantitatively demonstrates the increased parenchymal compliance and reduction in airway caliber that occurs with decreased parenchymal support from hypoinflated obstructed alveoli. This study provides a building block from which models of an entire lung can be developed in a computationally tenable manner that would simulate heterogeneous pulmonary mechanical interdependence. Such multiscale models could provide fundamental insight toward the development of protective ventilation strategies to reduce the incidence or severity of ventilator-induced lung injury. NEW & NOTEWORTHY A destabilized lung leads to airway and alveolar collapse that can result in catastrophic pulmonary failure. This study elucidates the micromechanical effects of alveolar collapse and determines its range of influence on neighboring collapsible airways. A mesoscale analysis reveals a master relationship that can that can be used in a computationally efficient manner to quantitatively model alveolar mechanical heterogeneity that exists in acute respiratory distress syndrome (ARDS), which predisposes the lung to volutrauma and/or atelectrauma. This analysis may lead to computationally tenable simulations of heterogeneous organ-level mechanical interactions that can illuminate novel protective ventilation strategies to reduce ventilator-induced lung injury.

Pulmonary Smooth Muscle in Vertebrates: A Comparative Review of Structure and Function

Although the airways of vertebrates are diverse in shape, complexity, and function, they all contain visceral smooth muscle. The morphology, function, and innervation of this tissue in airways is reviewed in actinopterygians, lungfish, amphibians, non-avian reptiles, birds, and mammals. Smooth muscle was likely involved in tension regulation ancestrally, and may serve to assist lung emptying in fishes and aquatic amphibians, as well as maintain internal lung structure. In certain non-avian reptiles and anurans antagonistic smooth muscle fibers may contribute to intrapulmonary gas mixing. In mammals and birds, smooth muscle regulates airway caliber, and may be important in controlling the distribution of ventilation at rest and exercise, or during thermoregulatory and vocal hyperventilation. Airway smooth muscle is controlled by the autonomic nervous system: cranial cholinergic innervation generally causes excitation, cranial non-adrenergic, non-cholinergic innervation causes inhibition, and spinal adrenergic (SA) input causes species-specific, often heterogeneous contractions and relaxations.

Study on absolute eosinophil count correlation with severity of bronchial asthma

Background: Bronchial asthma is defined as chronic inflammatory disease of the airways that is characterized by increased responsiveness of the tracheobronchial tree to a multiplicity of stimuli. Eosinophil infiltration is a characteristic feature of asthmatic airways. It presents as an obstructive type of ventilator defect usually diagnosed from a reduced FEV1% (Forced Expiratory Volume) or from a reduced peak expiratory flow (PEF) associated with reduced airway caliber during expiration. Allergen inhalation results in a marked increase in activated eosinophils in the airways. Correlation between the degree of bronchial hyperresponsiveness (a cardinal feature of asthma) and peripheral blood eosinophilia has been observed in patients with dual response following allergen challenge.Methods: The study comprises a total number of 50 bronchial asthma patients of both sexes (male and female) between the age groups of 13-65 years. Based on severity, asthma patients were classified into mild, moderate and severe asthmatics, assessed by FEV1% computerized Spirometry Helios model number 701, recorders and medicare system. Peripheral blood sample was collected from each patient for absolute eosinophil count, the count was done on the same day.Results: The mean±SD absolute eosinophil count of 50 patients is 330±88.64 which is slightly above normal (300 cells/mm3). Author found that the mean±SD absolute eosinophil count of 405±83.16 in severe asthma patients is quite high, corresponding with a steep decline in the FEV1% 45.3±12.6.Conclusions: Absolute eosinophil count and FEV1% are important indicators of bronchial asthma severity and can even be used to predict disease progression.