Person:

Tsuda, Akira

Background: An intriguing biologic process in most adult mammals is post-pneumonectomy lung regeneration, that is, the removal of one lung (pneumonectomy) results in the rapid compensatory growth of the remaining lung. The spatial dependence and metabolic activity of the rodent lung during compensatory lung regeneration is largely unknown. Methods: To determine if murine lung regeneration could be detected in vivo, we studied inbred mice 3, 7, 14, and 21 days after left pneumonectomy. The remaining lung was imaged using microCT as well as the glucose tracer 2-deoxy-2-[18 F]fluoro-d-glucose (18FDG) and positron-emission tomography (PET). Because of the compliance of the murine chest wall, reproducible imaging required orotracheal intubation and pressure-controlled ventilation during scanning. Results: After left pneumonectomy, the right lung progressively enlarged over the first 3 weeks. The cardiac lobe demonstrated the greatest percentage increase in size. Dry weights of the individual lobes largely mirrored the increase in lung volume. PET/CT imaging was used to identify enhanced metabolic activity within the individual lobes. In the cardiac lobe, 18FDG uptake was significantly increased in the day 14 cardiac lobe relative to preoperative values (p < .05). In contrast, the 18FDG uptake in the other three lobes was not statistically significant at any time point. Conclusions: We conclude that the cardiac lobe is the dominant contributor to compensatory growth after murine pneumonectomy. Further, PET/CT scanning can detect both the volumetric increase and the metabolic changes associated with the regenerative growth in the murine cardiac lobe.

In many mammals, including rodents and humans, removal of one lung results in the compensatory growth of the remaining lung; however, the mechanism of compensatory lung growth is unknown. Here, we investigated the changes in morphology and phenotype of pleural cells after pneumonectomy. Between days 1 and 3 after pneumonectomy, cells expressing α-smooth muscle actin (SMA), a cytoplasmic marker of myofibroblasts, were significantly increased in the pleura compared to surgical controls (p < .01). Scanning electron microscopy of the pleural surface 3 days post-pneumonectomy demonstrated regions of the pleura with morphologic features consistent with epithelial-mesenchymal transition (EMT); namely, cells with disrupted intercellular junctions and an acquired mesenchymal (rounded and fusiform) morphotype. To detect the migration of the transitional pleural cells into the lung, a biotin tracer was used to label the pleural mesothelial cells at the time of surgery. By post-operative day 3, image cytometry of post-pneumonectomy subpleural alveoli demonstrated a 40-fold increase in biotin+ cells relative to pneumonectomy-plus-plombage controls (p < .01). Suggesting a similar origin in space and time, the distribution of cells expressing biotin, SMA, or vimentin demonstrated a strong spatial autocorrelation in the subpleural lung (p < .001). We conclude that post-pneumonectomy compensatory lung growth involves EMT with the migration of transitional mesothelial cells into subpleural alveoli.

A 33-year-old woman underwent a right-sided pneumonectomy in 1995 for treatment of a lung adenocarcinoma. As expected, there was an abrupt decrease in her vital capacity, but unexpectedly, it increased during the subsequent 15 years. Serial computed tomographic (CT) scans showed progressive enlargement of the remaining left lung and an increase in tissue density. Magnetic resonance imaging (MRI) with the use of hyperpolarized helium-3 gas showed overall acinar-airway dimensions that were consistent with an increase in the alveolar number rather than the enlargement of existing alveoli, but the alveoli in the growing lung were shallower than in normal lungs. This study provides evidence that new lung growth can occur in an adult human.

Despite nearly a half century of studies, it has not been fully understood how pulmonary alveoli, the elementary gas exchange units in mammalian lungs, inflate and deflate during respiration. Understanding alveolar dynamics is crucial for treating patients with pulmonary diseases. In-vivo, real-time visualization of the alveoli during respiration has been hampered by active lung movement. Previous studies have been therefore limited to alveoli at lung apices or subpleural alveoli under open thorax conditions. Here we report direct and real-time visualization of alveoli of live intact mice during respiration using tracking X-ray microscopy. Our studies, for the first time, determine the alveolar size of normal mice in respiration without positive end expiratory pressure as 58 ± 14 (mean ± s.d.) μm on average, accurately measured in the lung bases as well as the apices. Individual alveoli of normal lungs clearly show heterogeneous inflation from zero to ~25% (6.7 ± 4.7% (mean ± s.d.)) in size. The degree of inflation is higher in the lung bases (8.7 ± 4.3% (mean ± s.d.)) than in the apices (5.7 ± 3.2% (mean ± s.d.)). The fraction of the total tidal volume allocated for alveolar inflation is 34 ± 3.8% (mean ± s.e.m). This study contributes to the better understanding of alveolar dynamics and helps to develop potential treatment options for pulmonary diseases.

Abstract The critical care management of pleural air leaks can be challenging in all patients, but particularly in patients on mechanical ventilation. To investigate the effect of central airway pressure and pleural pressure on pulmonary air leaks, we studied orotracheally intubated mice with pleural injuries. We used clinically relevant variables – namely, airway pressure and pleural pressure – to investigate flow through peripheral air leaks. The model studied the pleural injuries using a pressure‐decay maneuver. The pressure‐decay maneuver involved a 3 sec ramp to 30 cmH20 followed by a 3 sec breath hold. After pleural injury, the pressure‐decay maneuver demonstrated a distinctive airway pressure time history. Peak inflation was followed by a rapid decrease to a lower plateau phase. The decay phase of the inflation maneuver was influenced by the injury area. The rate of pressure decline with multiple injuries (28 ± 8 cmH20/sec) was significantly greater than a single injury (12 ± 3 cmH2O/sec) (P < 0.05). In contrast, the plateau phase pressure was independent of injury surface area, but dependent upon transpulmonary pressure. The mean plateau transpulmonary pressure was 18 ± 0.7 cm H2O. Finally, analysis of the inflation ramp demonstrated that nearly all volume loss occurred at the end of inflation (P < 0.001). We conclude that the air flow through peripheral lung injuries was greatest at increased lung volumes and limited by peripheral airway closure. In addition to suggesting an intrinsic mechanism for limiting flow through peripheral air leaks, these findings suggest the utility of positive end‐expiratory pressure and negative pleural pressure to maintain lung volumes in patients with pleural injuries.