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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.

Airway remodelling and emphysema are major structural abnormalities in chronic obstructive pulmonary disease (COPD). In addition, pulmonary vascular remodelling may occur and contribute to pulmonary hypertension, a comorbidity of COPD. Increased cholinergic activity in COPD contributes to airflow limitation and, possibly, to inflammation and airway remodelling. This study aimed to investigate the role of acetylcholine in pulmonary inflammation and remodelling using an animal model of COPD. To this aim, guinea pigs were instilled intranasally with lipopolysaccharide (LPS) twice weekly for 12 weeks and were treated, by inhalation, with the long-acting muscarinic receptor antagonist tiotropium. Repeated LPS exposure induced airway and parenchymal neutrophilia, and increased goblet cell numbers, lung hydroxyproline content, airway wall collagen and airspace size. Furthermore, LPS increased the number of muscularised microvessels in the adventitia of cartilaginous airways. Tiotropium abrogated the LPS-induced increase in neutrophils, goblet cells, collagen deposition and muscularised microvessels, but had no effect on emphysema. In conclusion, tiotropium inhibits remodelling of the airways as well as pulmonary inflammation in a guinea pig model of COPD, suggesting that endogenous acetylcholine plays a major role in the pathogenesis of this disease.

All-trans retinoic acid (ATRA) is controversially discussed in emphysema therapy. We re-evaluated ATRA in the elastase model and hypothesised that beneficial effects should be reflected by increased alveolar surface area, elastin expression and downregulation of inflammatory mediators and matrix metalloproteinases (MMPs). Emphysema was induced by porcine pancreatic elastase versus saline in Sprague-Dawley rats. On days 26-37, rats received daily intraperitoneal injections with ATRA (500 μg · kg(-1) body weight) versus olive oil. Lungs were removed at day 38. Rat alveolar epithelial L2 cells were incubated with/without elastase followed by ATRA- or vehicle-treatment, respectively. ATRA only partially ameliorated structural defects. Alveolar walls exhibited irregular architecture: increased arithmetic mean thickness, reduction in surface coverage by alveolar epithelial cells type II. ATRA only partially restored reduced soluble elastin. It tended to increase the ratio of ED1(+):ED2(+) macrophages. Bronchoalveolar lavage (BAL) cells exhibited a proinflammatory state and high expression of interleukin-1β, cytokine-induced neutrophil chemoattractant-1, tumour necrosis factor-α, nuclear factor-κB, MMP-2, MMP-9, MMP-12, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 in emphysema, with ATRA exerting only few effects. MMP-7 was highly induced by ATRA in healthy but not in emphysematous lungs. ATRA reduced both MMP-2 and TIMP-1 activity in BAL fluid of emphysematous lungs. ATRA-therapy may bear the risk of unwanted side-effects on alveolar septal architecture in emphysematous lungs.

Chronic obstructive pulmonary disease (COPD) exhibits airflow obstruction that is not fully reversible. The importance of bronchoreversibility remains controversial. We hypothesised that an emphysematous phenotype of COPD would be associated with decreased bronchoreversibility. 544 patients randomised to the medical arm of the National Emphysema Treatment Trial formed the study group. Participants underwent multiple measurements of bronchoreversibility on a mean of four sessions over 1.91 yrs. They were also characterised by measures of symptoms, quality of life and quantitative measures of emphysema by computed tomography. Mean baseline forced expiratory volume in 1 s (FEV(1)) in this patient population is 24% predicted. 22.2% of patients demonstrated bronchoreversibility on one or more occasions using American Thoracic Society/European Respiratory Society criteria. Few patients (0.37%) had bronchoreversibility on all completed tests. Patients who demonstrated bronchoreversibility were more likely to be male, and have better lung function and less emphysema. 64% of patients demonstrated large (> or =400 mL) changes in forced vital capacity (FVC). In a severe emphysema population, bronchoreversibility as defined by change in FEV(1) is infrequent, varies over time, and is more common in males and those with less severe emphysema. Improvements in FVC, however, were demonstrated in the majority of patients.

Given the emerging physiological and clinical rationale for pharmacological lung-volume reduction, assessment of volume responses to bronchodilators is likely to be highly relevant in chronic obstructive pulmonary disease (COPD). The authors examined the magnitude of lung-volume reduction after acute bronchodilator treatment in patients with advanced emphysema. Eighty-four stable patients with emphysema (mean+/-SEM forced expiratory volume in one second (FEV1): 32+/-1% predicted) performed spirometry and body plethysmography before and 15-30 min after 200 microg salbutamol. Only irreversible patients with a postbronchodilator change in FEV1 <10% pred were considered in this study. Postsalbutamol, the majority of subjects (83%) had significant improvements in one or more lung volumes: on average, residual volume (RV), functional residual capacity (FRC), inspiratory capacity (IC), forced vital capacity and slow vital capacity changed by -18+/-2, -10+/-1, 8+/-1, 9+/-1 and 7+/-1% pred (p<0.0005 each). Total lung capacity (TLC) decreased 0.12+/-0.04 L (p<0.01). Change in IC reflected change in FRC (r=-0.60, p<0.0005), but more strongly in the 57% of patients with no significant change in TLC (r=-0.93, p<0.0005). The magnitude and frequency of volume responses were greatest in patients with the most severe COPD; for example, RV decreased by 0.51+/-0.09 L (23+/-4% pred) and 0.27+/-0.04 L (14+/-2% pred) in severe and moderate subgroups, respectively. Significant reductions in lung hyperinflation occurred in the absence of a change in forced expiratory volume in one second after low-dose salbutamol in a majority of patients with advanced emphysema; the greatest changes occurred in those with the most severe disease.

A 44 yr-old female with severe pulmonary emphysema and reduced alpha-1-protease inhibitor (alpha1-PI) serum levels developed an acute anaphylactic reaction following the third intravenous infusion of human alpha1-PI which was administered to prevent the progression of pulmonary emphysema. Specific immunoglobulin E-antibodies against human alpha1-PI could be demonstrated in the patient's serum using an enzyme allergosorbent test. Because of the risk of further severe anaphylactic reaction, the replacement therapy with alpha1-PI was discontinued. Physicians should be aware of this rare complication.

Human neutrophils are a likely source of elastase in the pathogenesis of human pulmonary emphysema. A study was undertaken to determine whether emphysema, induced in hamsters by intratracheal treatment with human neutrophil elastase (HNE), could be ameliorated by intratracheal instillation of succinyl-alanyl-alanyl-prolyl-valine-chloromethyl ketone (CMK). One mg of CMK was given to hamsters 1 h before 300 or 360 micrograms HNE or 1 h or 4 h after 360 micrograms HNE. The animals were studied eight weeks after treatment. The CMK given 4 h after HNE did not ameliorate the emphysema. The CMK given 1 h before HNE, ameliorated the development of emphysema but not bronchial secretory cell metaplasia. A molar ratio of instilled CMK to HNE of 128 was required for 50% in vivo effectiveness in ameliorating emphysema. Clearance studies indicated that 6.9% of the instilled CMK could be lavaged from the lungs 1 h after instillation. Therefore, an 8.9 to 1 molar ratio of lavageable CMK to HNE, at the time of HNE instillation, resulted in 50% protection. Using an in vitro assay with 3H-elastin as substrate, a 3 to 1 molar ratio of CMK to HNE was required to inhibit 50% of the elastolytic activity; 14% of the activity remained with an 18 to 1 molar ratio of CMK to HNE. Study of the in vivo effectiveness of anti-elastases, given as pretreatment in ameliorating HNE-induced emphysema and secretory cell metaplasia, is a reasonable bioassay, which may be used as a step in evaluating such agents for possible use in the prevention of human disease.