Expiration rate drives human airway design

Analyses of human airway architecture based on calculations of airflow resistance or energy dissipation suggest that the branching pattern is not optimized for minimizing energy loss by flow dissipation during respiration. Airway flow dissipates only a few percent of the total body work during normal breathing, so branching patterns deviate from minimum energy loss to also optimize other physiological needs. Studies of airway performance often record some measure of expiration, such as FEV1 (Forced Expiratory Volume in 1 s), because airway constriction during expiration limits the rate of rapid respiration. We posit that lung structure is optimized for the rate of expiration as well as minimum energy loss. By increasing the daughter-to-parent airway diameter ratio (h) from 0.794 (corresponding to the energy minimum for symmetrically branching airways) to 0.85 (the observed value in humans) luminal pressures at airway generations 4-15 were substantially increased during exercise (a 4.5 and 15 cmH₂O increase during moderate and heavy exercise, respectively). Values of h somewhat larger than 0.794 help airways remain open during expiration by increasing both viscous pressure drop and convective acceleration pressure drop. Asymmetric bifurcations also exhibit higher proximal airway pressures than symmetric ones, but the improvement was not large.     

Circadian rhythm of airways caliber and its autonomic modulation

ABSTRACT

The autonomic nervous system (ANS) is one of the effector pathways for circadian variation of many physiological parameters. Autonomic tone and airways caliber have been reported to exhibit circadian variation in separate studies. A simultaneous investigation of heart rate variability (HRV) and airway caliber might ascertain how airway caliber is modulated by autonomic tone. This study was planned to identify the variations in airway caliber and autonomic function tone during a 24-hour span. A total of 56 healthy male subjects with almost similar daily routines were studied. Time domain, frequency domain and nonlinear analysis of R-R interval from 5 min electrocardiogram (ECG) was done seven times during the daytime wake span at 3-hour intervals starting at 05:00 h in the morning until 23:00 h in the night. Simultaneously peak expiratory flow rate (PEFR) was determined using a mini Wright’s peak flow meter. Rhythmometric analysis was done for PEFR and HRV parameters. Significant circadian variation in low frequency (LF) and high frequency (HF) variance was identified in this group of healthy subjects. The circadian rhythm of LF variance was characterized by a gradual increase and corresponding reciprocal change in HF variance from morning until night. The LF/HF ratio and SD2/SD1 ratio reflecting sympatho-vagal balance showed low to high values from morning to evening. The acrophase of the PEFR temporal pattern is similar to that of LF power and almost opposite in phase to that of HF power. PEFR is positively correlated with LF power. The circadian rhythm of airway caliber co-varies with cardiac autonomic tone. It appears that the temporal pattern of cardiac autonomic tone precedes in time that of airways caliber, thereby suggesting the latter operates under the modulatory effect of the 24-hour pattern in sympatho-vagal balance.     

Effect of exercise-induced hyperventilation on airway resistance and cycling endurance

The purpose of the present study was to investigate the effect of exercise induced hyperventilation and hypocapnia on airway resistance (R _aw), and to try to answer the question whether a reduction of R _aw is a mechanism contributing to the increase of endurance time associated with a reduction of exercise induced hyperventilation as for example has been observed after respiratory training. Eight healthy volunteers of both sexes participated in the study. Cycling endurance tests (CET) at 223 (SD 47) W, i.e. at 74 (SD 5)% of the subject's peak exercise intensity, breathing endurance tests and body plethysmograph measurements of pre- and postexercise R _aw were carried out before and after a 4-week period of respiratory training. In one of the two CET before the respiratory training CO₂ was added to the inspired air to keep its end-tidal concentration at 5.4% to avoid hyperventilatory hypocapnia (CO₂-test); the other test was the control. The pre-exercise values of specific expiratory R _aw were 8.1 (SD 2.8), 6.8 (SD 2.6) and 8.0 (SD 2.1) cm H₂O · s and the postexercise values were 8.5 (SD 2.6), 7.4 (SD 1.9) and 8.0 (SD 2.7) cm H₂O · s for control CET, CO₂-CET and CET after respiratory training, respectively, all differences between these tests being nonsignificant. The respiratory training significantly increased the respiratory endurance time during breathing of 70% of maximal voluntary ventilation from 5.8 (SD 2.9) min to 26.7 (SD 12.5) min. Mean values of the cycling endurance time (t _cend) were 22.7 (SD 6.5) min in the control, 19.4 (SD 5.4) min in the CO₂-test and 18.4 (SD 6.0) min after respiratory training. Mean values of ventilation ( _E) during the last 3␣min of CET were 123 (SD 35.8) l · min⁻¹ in the control, 133.5 (SD 35.1) l · min⁻¹ in the CO₂-test and 130.9 (SD 29.1) l · min⁻¹ after respiratory training. In fact, six subjects ventilated more and cycled for a shorter time, whereas two subjects ventilated less and cycled for a longer time after the respiratory training than in the control CET. In general, the subjects cycled longer the lower the _E, if all three CET are compared. It is concluded that R _aw measured immediately after exercise is independent of exercise-induced hyperventilation and hypocapnia and is probably not involved in limiting t _cend, and that t _cend at a given exercise intensity is shorter when _E is higher, no matter whether the higher _E occurs before or after respiratory training or after CO₂ inhalation. Accepted: 11 September 1996     

Direct numerical simulation of expiratory crackles: Relationship between airway closure dynamics and acoustic fluctuations

This paper investigates the relationship between airway closure dynamics and acoustic fluctuations in expiratory crackles using direct numerical simulation. A unified mathematical model is proposed to deal with flow in an airway, elastic deformation of the airway wall, surface tension driven motion of the liquid film that lines the airway, and their acoustic fluctuations because of material compressibility. Airway closure is induced by increasing the surrounding pressure, then the source of the pressure fluctuations is measured over time. Our results show that the airway closure occurs suddenly because of a bridge formation of the liquid film, and high energy transfer occurs between the kinetic energy, the surface energy of the liquid interface, and the elastic energy of the airway wall, invoking a large acoustic fluctuation that causes the expiratory crackles. Nonlinear behavior is observed in terms of the airway wall stiffness; the dynamic motion of the airway closure becomes moderate and both the energy transfer and acoustic fluctuations are dramatically reduced with an increase in airway wall stiffness.     

Effects of ophiopogonin D and spicatoside A derived from Liriope Tuber on secretion and production of mucin from airway epithelial cells

In the present study, we investigated whether aqueous extract of Liriope Tuber, ophiopogonin D and spicatoside A derived from Liriope Tuber affect basal or phorbol ester (phorbol 12-myristate 13-acetate, PMA)-induced airway mucin production and secretion from airway epithelial cells. Confluent NCI-H292 cells were treated with each agent for 24 h (basal production) or pretreated with each agent for 30 min and then stimulated with PMA for 24 h (PMA-induced production and secretion), respectively. MUC5AC airway mucin production and secretion were measured by ELISA. The results were as follows: (1) aqueous extract of Liriope Tuber stimulated basal mucin production and did not inhibit but increased PMA-induced mucin production; (2) ophiopogonin D and spicatoside A stimulated basal mucin production and did not inhibit but increased PMA-induced mucin production; (3) two compounds increased PMA-induced mucin secretion. These results suggest that ophiopogonin D and spicatoside A can increase mucin production and secretion, by directly acting on airway epithelial cells and, at least in part, explain the traditional use of aqueous extract of Liriope Tuber as expectorants in diverse inflammatory pulmonary diseases.     

The TMEM16A chloride channel as an alternative therapeutic target in cystic fibrosis

Cystic fibrosis (CF), a multiorgan genetic disease, is caused by loss of function of CFTR, a cAMP-regulated anion channel. In CF airway epithelia, defective Cl⁻ and bicarbonate secretion impairs mucociliary clearance and other innate defense mechanisms, favoring the colonization of the lungs by highly virulent bacteria. The airway epithelium expresses TMEM16A, a second type of Cl⁻ channel that is activated by cytosolic Ca²⁺. TMEM16A is particularly expressed in goblet cells. This specific localization could be important in the release and hydration of mucins. Activation of TMEM16A with pharmacological agents could circumvent the primary defect in CF. This strategy needs to be carefully designed and tested to avoid possible undesired effects due to the expression of TMEM16A in other cell types such as bronchial smooth muscle cells.This article is part of a Directed Issue entitled: Cystic Fibrosis: From o-mics to cell biology, physiology, and therapeutic advances.     

The presence of serotonin in cigarette smoke – a possible mechanistic link to 5-HT-induced airway inflammation

We previously reported the involvement of serotonin (5-HT) metabolism in cigarette smoke-induced oxidative stress in rat lung in vivo. Here, we report cigarette smoke as a source of serotonin (5-HT) to the airways and aim at investigating the effects of 5-HT on oxidative stress and inflammation in human bronchial epithelial cells (BEAS-2B). A 5-HT analog was identified to be present in aqueous phase cigarette smoke using the LC-MS/MS approach, which was later confirmed by a 5-HT enzyme-linked immune assay (EIA). Furthermore, exposure to 5-HT caused a time-dependent elevation of intracellular ROS level, which was blocked in the presence of apocynin (a NOX inhibitor). In support, the immunoblot analysis indicated that there was an increase in the expression of NOX2 time-dependently. 5-HT-induced elevation of IL-8 at both mRNA and protein levels was observed, which was inhibited by TEMPOL (a free radical scavenger), and inhibitors for p38 MAPK (SB203580) and ERK (U0126), in line with the time-dependent phosphorylation of p38 MAPK and ERK. In conclusion, our findings suggest that 5-HT presented in bronchial epithelium of smokers may be involved in cigarette smoke-induced oxidative stress and inflammation via activation of p38 MAPK and ERK pathway after the formation of free radicals.     

TLR-7 agonist attenuates airway reactivity and inflammation through Nrf2-mediated antioxidant protection in a murine model of allergic asthma

Toll-like receptors (TLRs) through innate immune system recognize pathogen associated molecular patterns and play an important role in host defense against bacteria, fungi and viruses. TLR-7 is responsible for sensing single stranded nucleic acids of viruses but its activation has been shown to be protective in mouse models of asthma. The NADPH oxidase (NOX) enzymes family mainly produces reactive oxygen species (ROS) in the lung and is involved in regulation of airway inflammation in response to TLRs activation. However, NOX-4 mediated signaling in response to TLR-7 activation in a mouse model of allergic asthma has not been explored previously. Therefore, this study investigated the role TLR-7 activation and downstream oxidant–antioxidant signaling in a murine model of asthma. Mice were sensitized with ovalbumin (OVA) intraperitoneally and treated with TLR-7 agonist, resiquimod (RSQ) intranasally before each OVA challenge from days 14 to 16. Mice were then assessed for airway reactivity, inflammation, and NOX-4 and nuclear factor E2-related factor 2 (Nrf2) related signaling [inducible nitric oxide synthase (iNOS), nitrotyrosine, lipid peroxides and copper/zinc superoxide dismutase (Cu/Zn SOD)]. Treatment with RSQ reduced allergen induced airway reactivity and inflammation. This was paralleled by a decrease in ROS which was due to induction of Nrf2 and Cu/Zn SOD in RSQ treated group. Inhibition of MyD88 reversed RSQ-mediated protective effects on airway reactivity/inflammation due to reduction in Nrf2 signaling. SOD inhibition produced effects similar to MyD88 inhibition. The current study suggests that TLR-7 agonist is beneficial and may be developed into a therapeutic option in allergic asthma.     

Th1 and Th2 cells are required for both eosinophil- and neutrophil-associated airway inflammatory responses in mice

Most current animal models focus on eosinophil-mediated asthma, despite compelling evidence that a neutrophil-mediated disease occurs in some asthma patients. Using intranasal challenge of mice sensitized either orally or nasally with whole peanut protein extract in the presence of cholera toxin, we developed mouse models of eosinophil- and neutrophil-mediated asthma, respectively. In this study, mice deficient in Th1 (IL-12 and IFN-gamma) or Th2 (IL-4 and IL-13) pathways were used to characterize the role played by Th1 and Th2 cytokines during the initial priming phase in the two models. Antigen-specific Ab responses were controlled primarily by Th2 cytokines in mice sensitized by the oral route, whereas Th1 cytokines appeared to play a predominant role in mice sensitized by the nasal route. Furthermore, the absence of key Th1 or Th2 cytokines during the initial phase of priming reduced lung reactivity in both mouse models of airway inflammation.     

Cytoskeleton dynamics: fluctuations within the network

Out-of-equilibrium systems, such as the dynamics of a living cytoskeleton (CSK), are inherently noisy with fluctuations arising from the stochastic nature of the underlying biochemical and molecular events. Recently, such fluctuations within the cell were characterized by observing spontaneous nano-scale motions of an RGD-coated microbead bound to the cell surface [Bursac et al., Nat. Mater. 4 (2005) 557-561]. While these reported anomalous bead motions represent a molecular level reorganization (remodeling) of microstructures in contact with the bead, a precise nature of these cytoskeletal constituents and forces that drive their remodeling dynamics are largely unclear. Here, we focused upon spontaneous motions of an RGD-coated bead and, in particular, assessed to what extent these motions are attributable to (i) bulk cell movement (cell crawling), (ii) dynamics of focal adhesions, (iii) dynamics of lipid membrane, and/or (iv) dynamics of the underlying actin CSK driven by myosin motors.