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Lung volume reduction surgery (LVRS), the removal of damaged, hyperexpanded lung, has been shown to improve respiratory function in many patients with end-stage emphysema. We report the results of an animal study using a new transbronchoscopic alternative to LVRS in which a washout solution and fibrin-based glue are used to collapse, seal, and scar target regions of abnormal lung. Twelve sheep had static and dynamic lung functions measured at baseline. Emphysema was produced by inhaled papain (7,000 U/wk x 4 wk), resulting in a significant increase of lung volumes, compliance, and airway resistance. The animals were then divided into three treatment groups of four animals, and underwent surgical volume reduction (SVR), bronchoscopic volume reduction (BVR), or bronchoscopy alone (Sham-BVR). Response to each intervention was assessed 8 to 12 wk after treatment by measuring lung function and examining lung tissue. BVR and SVR groups responded with significant and similar decreases in TLC and residual volume (RV). Tissue examination demonstrated that BVR caused collapse of the lung with focal scarring in 11 of 20 target territories (55% success rate). Three of the 11 target zones developed sterile abscesses. Postprocedure complications were less frequent with BVR than with SVR. This pilot study suggests that lung volume reduction can be achieved in animals without surgery using a bronchoscopic approach and a novel fibrin-based glue system. BVR has the potential for simplifying volume reduction, extending indications, and reducing morbidity, mortality, and costs in humans.

Physiological and radiological criteria are both used to identify candidates for LVRS. This study compares the predictive value of these screening techniques among patients with homogeneous (Ho) and heterogeneous (He) emphysema. Preoperative inspiratory lung conductance (G(Li)) during spontaneous breathing and quantitative radioisotope V/Q scan (QVQS) results were available for 48 of 50 patients undergoing bilateral LVRS for emphysema. Ho disease (n = 21) was defined by QVQS as an upper/lower perfusion ratio (ULPR) between 0.75 and1.25. G(Li) correlated with 6-mo improvement in FEV(1) (DeltaFEV(1)-6) (r = 0.53, p < 0.001) for the entire cohort, and for patients with both Ho (n = 21, r = 0.56, p = 0.015) and He disease (n = 27, r = 0.46, p = 0.017). ULPR correlated less well with DeltaFEV(1)-6 (n = 48, r = -0.38; p = 0.008) for the cohort, and was significantly correlated with outcomes only in the subgroup of patients with He disease (r = -0.40, p = 0.04). Multivariate regression demonstrated that by combining G(Li) and ULPR criteria, 33% of the DeltaFEV(1)-6 response could be accounted for. We conclude that both physiological and radiological criteria help identify appropriate candidates for LVRS. G(Li) best identifies patients with Ho emphysema who may benefit from surgery, but would be excluded on the basis of strictly radiological criteria. ULPR helps identify patients with He disease that improves with surgery, despite unfavorable G(Li).

Spirometry and pulmonary mechanics were measured pre- and postoperatively in 37 patients undergoing bilateral lung volume reduction surgery (LVRS). The relative contributions of changes in compliance (CL), recoil pressures (PTLC), small airway conductance (Gu), and airway closing pressures (Ptm') to changes in expiratory flows were examined with a Taylor series expansion of the Pride- Permutt model of flow limitation. The resulting variational expression, deltaVmax = GudeltaPel + PeldeltaGu - GudeltaPtm' - Ptm'deltaGu - deltaGudeltaPtm', was then used to describe how the peak flow rate (Vmax) depends on preoperative Gu, P TLC, Ptm', and on changes (delta) in these parameters after surgery. After LVRS, both FEV(1) and Vmax increased significantly ( DeltaFEV(1) = 28 +/- 44%; DeltaVmax = 78 +/- 132%), and changes in FEV(1) and Vmax correlated closely (r = 0.74, p < 0.001). Among responders (DeltaFEV(1) > or = 12%; n = 19; DeltaFEV(1) = 60 +/- 38%), PTLC increased (8.8 +/- 2.8 to 12.2 +/- 4.7 cm H2O) and the time constant for expiration (tau = CL/Gu) decreased (2.67 +/- 0.62 to 2.35 +/- 0.55 s), while Ptm', CL, and Gu did not change. GudeltaPel, the change in recoil weighted by preoperative conductance upstream of the flow-limiting site, accounted for 72% of the improvement in Vmax. Among nonresponders ( DeltaFEV(1) = -6 +/- 15%, n = 18), tau increased significantly, contributing to a decline in FEV(1)/FVC ratio. PeldeltaGu decreased (-0.25 +/- 0.68, p = 0.013), accounting for all of the decline in Vmax. This analysis suggests that (1) improvement in expiratory flows after LVRS is largely due to increases in recoil pressure; (2) large improvements in FEV(1) can occur without changes in Gu or Ptm', arguing that LVRS has little effect on airway resistance or closure; and (3) large changes in PTLC can occur without changes in CL, supporting arguments of Fessler and Permutt (Am J Respir Crit Care Med 1998;157:715-722) that "resizing of the lung to chest wall" is the primary mechanism by which LVRS improves lung function.

Mechanical interactions between lung and chest wall are important determinants of respiratory function. When chest wall expansion during maximal inhalation generates insufficiently negative pleural pressures, the lungs remain functionally underinflated; this may be termed functional restriction. To explore mechanisms and effects of functional restriction in patients with emphysema, and to predict effects of single lung transplantation and lung volume reduction surgery (LVRS), we used a computational model based on standard physiology and measurements from individual patients. The model's lungs, separated by a compliant mediastinum, exhibit flow limitation according to the equal pressure point approach of Mead and coworkers. Pulmonary elastic recoil pressure is characterized by an exponential equation modified to reflect airway closure. Simulated respiratory maneuvers can be specified by variations in flow or pressure at the airway opening or in respiratory muscle activation. Model simulations successfully mimic recordings from individual patients. Input parameter values may then be altered to predict effects of surgical interventions in these same patients. The model simulations show the following. Single lung transplantation in emphysema can cause functional restriction of the normal transplanted lungs, and larger transplanted lungs may perform less well than smaller ones. LVRS improves lung and chest wall function in emphysema, but not in normal states. Surgical reduction of the native emphysematous lung after single lung transplantation can reduce functional restriction of the transplant and thereby improve its function.

Asthmatic airways are infiltrated with inflammatory cells that release mediators and cytokines into the microenvironment. In this study, we evaluated the distribution of CD45-positive leukocytes and eosinophils in lung tissue from five patients who died with severe asthma compared with five patients with cystic fibrosis. For morphometric analysis, the airway wall was partitioned into an "inner" area (between basement membrane and smooth muscle) and an "outer" area (between smooth muscle and alveolar attachments). Large airways (with a perimeter greater than 3.0 mm) from patients with asthma or cystic fibrosis had a greater density of CD45-positive cells (p < 0.05) and eosinophils (p < 0.001) in the inner airway region compared with the same airway region in small airways. Furthermore, in small airways, asthmatic lungs showed a greater density of CD45-positive cells (p < 0.01) and eosinophils (p < 0.01) in the outer compared with the inner airway wall region. These observations indicate that there are regional variations in inflammatory cell distribution within the airway wall in patients with asthma that are not observed in airways from patients with cystic fibrosis. We speculate that this inflammatory cell density in peripheral airways in severe asthma may relate to the peripheral airway obstruction characteristic of this condition.

Severe alpha-1-antitrypsin deficiency is the only proven genetic risk factor for chronic obstructive pulmonary disease (COPD). We have assembled a cohort of 44 probands with severe, early-onset COPD, who do not have severe alpha-1-antitrypsin deficiency. A surprisingly high prevalence of females (79.6%) was found. Assessment of the risk to relatives of these early-onset COPD probands for airflow obstruction and chronic bronchitis was performed to determine whether significant familial aggregation for COPD, independent of alpha-1-antitrypsin deficiency, could be demonstrated. First- degree relatives of early-onset COPD probands had significantly lower FEV1 and FEV1/FVC values than control subjects (p < 0.01), despite similar pack-years of smoking. Reduced spirometric values in first-degree relatives of early-onset COPD probands were found only in current or ex-cigarette smokers. The mean FEV1 in current or ex-smoking first-degree relatives was 76.1 +/- 20.9% predicted compared to 89.2 +/- 14.4% predicted in current or ex-smoking control subjects (p < 0.01); in lifelong nonsmokers, the mean FEV1 was 93.4% predicted for both control subjects and first-degree relatives of early-onset COPD probands. Generalized estimating equations, adjusting for age and pack-years of smoking, demonstrated increased odds of reduced FEV1 and chronic bronchitis in current or ex-smoking first-degree relatives of early-onset COPD probands. Using a new method to estimate relative risk from relative odds, we estimate that the relative risks for FEV1 below 60%, FEV1 below 80%, and chronic bronchitis are each approximately three in current or ex-smoking first-degree relatives of early-onset COPD probands. The increased risk to relatives of early-onset COPD probands for reduced FEV1 and chronic bronchitis, limited to current or ex-smokers, suggests genetic risk factor(s) for COPD that are expressed in response to cigarette smoking.