Modulation of airway surface liquid (ASL) pH has been proposed as a therapy for cystic fibrosis (CF). However, evidence that ASL pH is reduced in CF is limited and conflicting. The technical challenges associated with measuring ASL pH in vivo have precluded accurate measurements in humans. In order to address this deficiency, ASL pH was measured in vivo in children using a novel luminescent technology integrated with fibre-optic probes. Here we show that ASL pH in children with CF is similar to that of children without CF. Findings were supported by highly controlled direct pH measurements in primary human airway epithelial cell culture models, which also suggest that the potential ASL pH gradient produced by defective apical ion transport is balanced out by paracellular shunting of acid/base. Thus, reduced baseline ASL pH is unlikely to be an important pathobiological factor in early CF lung disease.

In vivo, breathing movements, including tidal and deep inspirations (DIs), exert a number of beneficial effects on respiratory system responsiveness in healthy humans that are diminished or lost in asthma, possibly as a result of reduced distension (strain) of airway smooth muscle (ASM). We used bronchial segments from pigs to assess airway responsiveness under static conditions and during simulated tidal volume oscillations with and without DI and to determine the roles of airway stiffness and ASM strain on responsiveness. To simulate airway dilations during breathing, we cycled the luminal volume of liquid-filled segments. Volume oscillations (15 cycles/min) were set so that, in relaxed airways, they produced a transmural pressure increase of approximately 5-10 cmH(2)O for tidal maneuvers and approximately 5-30 cmH(2)O for DIs. ACh dose-response curves (10(-7)-3 x 10(-3) M) were constructed under static and dynamic conditions, and maximal response and sensitivity were determined. Airway stiffness was measured from tidal trough-to-peak pressure and volume cycles. ASM strain produced by DI was estimated from luminal volume, airway length, and inner wall area. DIs produced substantial ( approximately 40-50%) dilation, reflected by a decrease in maximal response (P < 0.001) and sensitivity (P < 0.05). However, the magnitude of bronchodilation decreased significantly in proportion to airway stiffening caused by contractile activation and an associated reduction in ASM strain. Tidal oscillations, in comparison, had little effect on responsiveness. We conclude that DI regulates airway responsiveness at the airway level, but this is limited by airway stiffness due to reduced ASM strain.

Hillman NH, Kemp MW, Noble PB, Kallapur SG, Jobe AH. Sustained inflation at birth did not protect preterm fetal sheep from lung injury. Am J Physiol Lung Cell Mol Physiol 305: L446 -L453, 2013. First published July 19, 2013 doi:10.1152/ajplung.00162.2013.-Sustained lung inflations (SI) at birth may recruit functional residual capacity (FRC). Clinically, SI increase oxygenation and decrease need for intubation in preterm infants. We tested whether a SI to recruit FRC would decrease lung injury from subsequent ventilation of fetal, preterm lambs. The preterm fetus (128 Ϯ 1 day gestation) was exteriorized from the uterus, a tracheostomy was performed, and fetal lung fluid was removed. While maintaining placental circulation, fetuses were randomized to one of four 15-min interventions: 1) positive endexpiratory pressure (PEEP) 8 cmH 2O (n ϭ 4), 2) 20 s SI to 50 cmH2O then PEEP 8 cmH 2O (n ϭ 10), 3) mechanical ventilation at tidal volume (V T) 7 ml/kg (n ϭ 13), or 4) 20 s SI then ventilation at VT 7 ml/kg (n ϭ 13). Lambs were ventilated with 95% N 2/5% CO2 and PEEP 8 cmH 2O. Volume recruitment was measured during SI, and fetal tissues were collected after an additional 30 min on placental support. SI achieved a mean FRC recruitment of 15 ml/kg (range 8 -27). Fifty percent of final FRC was achieved by 2 s, 65% by 5 s, and 90% by 15 s, demonstrating prolonged SI times are needed to recruit FRC. SI alone released acute-phase proteins into the fetal lung fluid and increased mRNA expression of proinflammatory cytokines and acute-phase response genes in the lung. Mechanical ventilation further increased all markers of lung injury. SI before ventilation, regardless of the volume of FRC recruited, did not alter the acutephase and proinflammatory responses to mechanical ventilation at birth.

In healthy individuals, deep inspiration produces bronchodilation and reduced airway responsiveness, which may be a response of the airway wall to mechanical stretch. The aim of this study was to examine the in vitro response of isolated human airways to the dynamic mechanical stretch associated with normal breathing. Human bronchial segments (n = 6) were acquired from patients without airflow obstruction undergoing lung resection for pulmonary neoplasms. The side branches were ligated and the airways were mounted in an organ bath chamber. Airway narrowing to cumulative concentrations of acetylcholine (3 × 10(-6) M to 3 × 10(-3) M) was measured under static conditions and in the presence of "tidal" oscillations with intermittent "deep inspiration." Respiratory maneuvers were simulated by varying transmural pressure using a motor-controlled syringe pump (tidal 5 to 10 cmH(2)O at 0.25 Hz, deep inspiration 5 to 30 cmH(2)O). Airway narrowing was determined from decreases in lumen volume. Tidal oscillation had no effect on airway responses to acetylcholine which was similar to those under static conditions. Deep inspiration in tidally oscillating, acetylcholine-contracted airways produced potent, transient (<1 min) bronchodilation, ranging from full reversal in airway narrowing at low acetylcholine concentrations to ∼50% reversal at the highest concentration. This resulted in a temporary reduction in maximal airway response (P < 0.001), without a change in sensitivity to acetylcholine. Our findings are that the mechanical stretch of human airways produced by physiological transmural pressures generated during deep inspiration produces bronchodilation and a transient reduction in airway responsiveness, which can explain the beneficial effects of deep inspiration in bronchial provocation testing in vivo.