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Wnt/β-catenin signaling regulates progenitor cell fate decisions during lung development and in various adult tissues. Ectopic activation of Wnt/β-catenin signaling promotes tissue repair in emphysema, a devastating lung disease with progressive loss of parenchymal lung tissue. The identity of Wnt/β-catenin responsive progenitor cells and the potential impact of Wnt/β-catenin signaling on adult distal lung epithelial progenitor cell function in emphysema are poorly understood. Here, we used TCF/Lef:H2B/GFP reporter mice to investigate the role of Wnt/β-catenin signaling in lung organoid formation. We identified an organoid-forming adult distal lung epithelial progenitor cell population characterized by a low Wnt/β-catenin activity, which was enriched in club and alveolar epithelial type (AT)II cells. Endogenous Wnt/β-catenin activity was required for the initiation of multiple subtypes of distal lung organoids derived from the Wnt low epithelial progenitors. Further ectopic Wnt/β-catenin activation specifically led to an increase in alveolar organoid number; however, the subsequent proliferation of alveolar epithelial cells in the organoids did not require constitutive Wnt/β-catenin signaling. Distal lung epithelial progenitor cells derived from the mouse model of elastase-induced emphysema exhibited reduced organoid forming capacity. This was rescued by Wnt/β-catenin signal activation, which largely increased the number of alveolar organoids. Together, our study reveals a novel mechanism of lung epithelial progenitor cell activation in homeostasis and emphysema., (©2020 The Authors. Stem Cells published by Wiley Periodicals LLC on behalf of AlphaMed Press 2020.)

Palovarotene is an oral γ-selective retinoid agonist. In animal emphysema models, palovarotene reduced inflammation, promoted structural repair and functional improvement. REPAIR (Retinoid treatment of Emphysema in Patients on the α(1)-antitrypsin International Registry), was an investigator-initiated, double-blind, placebo-controlled randomised study to assess the safety and efficacy of 5 mg·day(-1) palovarotene given for 1 year to 262 patients with severe α(1)-antitrypsin deficiency and emphysema confirmed by computed tomography. Change in volume-adjusted 15th percentile point lung density from baseline in 1 year was the primary end-point; functional end-points were also regularly assessed. We randomly assigned 133 and 129 patients to placebo or palovarotene, respectively. Both groups were well matched for all baseline characteristics, including respiratory medications. 88% and 85% of patients completed 1 year of treatment with placebo and palovarotene, respectively. Palovarotene was generally well tolerated. In the study completers population, the placebo-corrected difference of lung density was -0.45 HU at week 28 (p=0.64) and -0.25 HU at week 52 (p=0.94). A nonsignificant treatment difference in most functional parameters of the lung in favour of the drug was observed over time suggesting potential pharmacological effects of palovarotene. Palovarotene 5 mg·day(-1) over 1 yr failed to show a significant benefit on lung density in moderate-to-severe emphysema secondary to severe α(1)-antitrypsin deficiency.

Background: Two randomised, double-blind, placebo-controlled trials have investigated the efficacy of IV alpha-1 antitrypsin (AAT) augmentation therapy on emphysema progression using CT densitometry., Methods: Data from these similar trials, a 2-center Danish-Dutch study (n = 54) and the 3-center EXAcerbations and CT scan as Lung Endpoints (EXACTLE) study (n = 65), were pooled to increase the statistical power. The change in 15th percentile of lung density (PD15) measured by CT scan was obtained from both trials. All subjects had 1 CT scan at baseline and at least 1 CT scan after treatment. Densitometric data from 119 patients (AAT [Alfalastin® or Prolastin®], n = 60; placebo, n = 59) were analysed by a statistical/endpoint analysis method. To adjust for lung volume, volume correction was made by including the change in log-transformed total lung volume as a covariate in the statistical model., Results: Mean follow-up was approximately 2.5 years. The mean change in lung density from baseline to last CT scan was -4.082 g/L for AAT and -6.379 g/L for placebo with a treatment difference of 2.297 (95% CI, 0.669 to 3.926; p = 0.006). The corresponding annual declines were -1.73 and -2.74 g/L/yr, respectively., Conclusions: The overall results of the combined analysis of 2 separate trials of comparable design, and the only 2 controlled clinical trials completed to date, has confirmed that IV AAT augmentation therapy significantly reduces the decline in lung density and may therefore reduce the future risk of mortality in patients with AAT deficiency-related emphysema., Trial Registration: The EXACTLE study was registered in ClinicalTrials.gov as 'Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients'; ClinicalTrials.gov Identifier: NCT00263887.

The objectives of the present study were to reappraise chest radiography for the diagnosis of emphysema, using computed tomography (CT) as the reference standard, and to establish whether or not chest radiography is useful for phenotyping chronic obstructive pulmonary disease (COPD). Patients (n = 154) who had undergone posteroanterior and lateral chest radiography and CT for diagnostic purposes were studied. CT data were scored for emphysema using the picture-grading method. Chest radiographs were examined independently by five raters using four criteria for emphysema that had been validated against lung pathology. These criteria were then used to assess the prevalence of emphysema in 458 COPD patients. Patients with and without evidence of emphysema were compared with regard to age, sex, smoking history, body mass index (BMI), forced expiratory volume in one second (FEV(1)), diffusing capacity of the lung for carbon monoxide (D(L,CO)) and health status. Chest radiography yielded a sensitivity of 90% and a specificity of 98% for emphysema. Of the 458 COPD patients, 245 showed radiological evidence of emphysema. Emphysemic patients had a significantly lower BMI, FEV(1) and D(L,CO), greater restriction of physical activity and worse quality of life than nonemphysemic patients. There was no difference across the two groups with regard to age, sex or smoking history. Chest radiography is a simple means of diagnosing moderate-to-severe emphysema. It is useful in phenotyping chronic obstructive pulmonary disease and may aid physicians in their choice of treatment.

A common feature of lung disorders with poor treatment options, including emphysema, is a failure to initiate a repair process of the alveolar epithelium. Several putative stem cell niches in the lung thought to be involved in lung homeostasis have been described. Apparently, under pathophysiological conditions these resident progenitor cells are unable to recover damaged alveolar epithelium, in particular in emphysema. The potential therapeutic effect of retinoic acid receptor agonists on various resident lung progenitor cells is reviewed.

Background: The burden of proteinases from inflammatory cells in the lung of subjects with type Pi ZZ of alpha-1-antitrypsin deficiency is higher than in those without the deficiency. Cross-sectional studies have shown increased levels of biomarkers of extracellular matrix degradation in vivo. Longitudinal variability of these biomarkers is unknown but desirable for clinical studies with proteinase inhibitors., Methods: We measured three different types of biomarkers, including desmosines, elastase-formed fibrinogen fragments and heparan sulfate epitope JM403, in plasma and urine for a period of 7 weeks in a group of 12 patients who participated in a placebo-controlled study to assess the safety of a single inhalation of hyaluronic acid., Results: Effect of study medication on any of the biomarkers was not seen. Baseline desmosines in plasma and urine correlated with baseline CO diffusion capacity (R = 0.81, p = 0.01 and R = 0.65, p = 0.05). Mean coefficient of variation within patients (CVi) for plasma and urine desmosines was 18.7 to 13.5%, respectively. Change in urinary desmosine levels correlated significantly with change in plasma desmosine levels (R = 0.84, p < 0.01). Mean CVi for fibrinogen fragments in plasma was 20.5% and for JM403 in urine was 27.8%. No correlations were found between fibrinogen fragments or JM403 epitope and desmosines., Conclusion: We found acceptable variability in our study parameters, indicating the feasibility of their use in an evaluation of biochemical efficacy of alpha-1-antitrypsin augmentation therapy in Pi Z subjects.

Rationale and Objectives: The authors assessed the progression of pulmonary emphysema by means of quantitative analysis of computed tomography images., Methods: Twenty-three patients suffering from emphysema due to an alpha 1-antitrypsin deficiency, aged 45 +/- 7 years and exsmokers, were scanned twice with a 1-year time interval. At 90% of the vital lung capacity, slices with a thickness of 1.5 mm were acquired at the level of the carina and 5 cm above the carina; slices with a thickness of 1 cm were acquired 5 cm below the carina. The entire lung was scanned spirally at a respiratory status, corresponding with 75% of the total lung capacity at baseline. The mean lung densities (MLD) were calculated in an objective manner with new analytic software featuring automated detection of the lung contours., Results: Mean lung densities decreased by 14.2 +/- 12.0 Hounsfield units (HU; P < 0.001) above the carina, by 18.1 +/- 14.4 HU (P < 0.001) at the carina level, by 23.6 +/- 15.0 HU (P < 0.001) below the carina, and by 12.8 +/- 22.2 HU (P < 0.01) for the entire lung. The decrease in MLD was most obvious in the lower lung lobes. For the same patient group, the annual decrease in the forced expiratory volume (FEV1) and the carbon monoxide-diffusion were 120 +/- 190 mL (P < 0.01) and 10 +/- 70 mmol/kg/minute ( P < 0.2), respectively. No significant correlation was found between the decrease in MLD and the decrease in FEV1., Conclusions: Progression of emphysema can be assessed in an objective manner based on the mean lung density (MLD), measured from computed tomography volume scans as well as from single-slice scans. Mean lung density has proved to be more sensitive than FEV1 and carbon monoxide-diffusion.

Secretory leukocyte inhibitor (SLPI) is a potent inhibitor of serine proteinases, but sensitive to oxidative inactivation due to a methionine residue in the active centre of the inhibitor. We compared the potency of an oxidation-resistant mutant of recombinant SLPI with native recombinant SLPI in lipopolysaccharide (LPS)-induced emphysema in the hamster. Application of this oxidation-resistant mutant reduced the induced emphysema by 70 and 85% in two separate series of experiments. In contrast, an equal amount of native rSLPI resulted in significantly lower inhibition, 30 and 23%, respectively (P = 0.002). To demonstrate the effect of oxygen radicals upon a single LPS instillation in the lungs, we measured anti-neutrophil elastase activity in lung lavage fluid at 10 and 24 h after the instillation of a mixture of LPS and native rSLPI. We found that residual native rSLPI was only 70 and 55% active, respectively. The rSLPI-mutant remained 93% active in a similar experiment. The native and mutant inhibitor showed equal potency against proteinases in a granule extract of hamster neutrophils. We conclude that the replacement of methionine by leucine in the inhibitory centre of rSLPI results in a decreased sensitivity to oxidative inactivation and that this alone is sufficient to explain the greater efficiency of the rSLPI-mutant in reducing the extent of LPS-induced emphysema.

The aim of this study was to determine whether lipopolysaccharide-induced elastase release from recruited neutrophils in the hamster lung would induce emphysema, measured by mean linear intercept (Lm) and bronchial mucus cell hyperplasia (BMCH), scored in tissue sections stained with periodic acid-Schiff. Lipopolysaccharide (LPS) was instilled transorally twice a week for up to 5 weeks in hamsters. At 4 weeks after seven LPS instillations, Lm amounted to 87.6 +/- 1.2 microns, while it was 68.3 +/- 1.5 microns after seven saline instillations (P less than 0.01). At 6 months after the sixth LPS instillation, the Lm of these lungs was 83.3 +/- 1.6 microns, indicating irreversible tissue destruction. LPS-treated hamsters showed marked to severe BMCH, which was most evident in large intrapulmonary airways. Instillations of highly selective inhibitor of hamster PMN elastase resulted in 50 per cent inhibition of LPS-induced emphysema. The development of BMCH was inhibited by approximately 35 per cent by this agent. To study the response in time of cellular infiltration after a single LPS instillation, the lungs of groups of four hamsters were lavaged at different time points. PMN recruitment showed peak values at 4 and 48 h after LPS instillation and returned to baseline values at 96 h. Simultaneous intratracheal instillation of LPS and anti-TNF alpha antiserum resulted in a considerable reduction of neutrophil influx into bronchoalveolar spaces in the first 6 h after instillation.