Respiratory Disorders

John J. Reilly, M.D.
Clinical Director, Division of Pulmonary and Critical Care Medicine
Medical Director, Pulmonary Rehabilitation Program
Associate Professor of Medicine, Harvard Medical School
jreilly@partners.org

John Reilly is the Clinical Director of the Division of Pulmonary and Critical Care Medicine and an Associate Professor of Medicine at Harvard Medical School. In this role, he is responsible for overseeing the organization of the clinical activities of the Division, including the outpatient practice in the Center for Chest Diseases, the Pulmonary Consultation Service and the Medical Intensive Care Unit. He also serves as the Medical Director of the Pulmonary Rehabilitation Program. He has served as a pulmonologist on the Lung Transplant Team since its inception in 1990. He also attends on the critical care service in the Surgical Intensive Care Units and maintains an active outpatient practice, with a particular interest in patients with chronic obstructive lung disease.

Dr. Reilly’s research interests center on various aspects of chronic obstructive lung disease. He currently is a Principal Investigator in two clinical research networks funded by the National Heart, Lung and Blood Institute: The National Emphysema Treatment Trial and the COPD Clinical Research network. In addition, he has active projects in the physiology of emphysema and lung volume reduction surgery, the genetics of chronic obstructive lung disease and in the development of functional genomic biomarkers of obstructive lung disease.

Publications

1. Moy, M. L., S. J. Mentzer, et al. (2003). "Ambulatory monitoring of cumulative free-living activity." IEEE Eng Med Biol Mag 22(3): 89-95.
   
   
2. Ingenito, E. P., S. H. Loring, et al. (2003). "Physiological characterization of variability in response to lung volume reduction surgery." J Appl Physiol 94(1): 20-30.
   
   This paper examines potential physiological mechanisms responsible for improvement after lung volume reduction surgery (LVRS). In 25 patients (63 +/- 9 yr; 11 men, 14 women), spirometry [forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC)], lung volumes [residual volume (RV) and total lung capacity (TLC)], small airway resistance, recoil pressures, and respiratory muscle contractility (RMC) were measured before and 4-6 mo after LVRS. Data were interpreted to assess how changes in each component of lung mechanics affect overall function. Among responders (DeltaFEV(1) > or = 12%; 150 ml), improvement was primarily due to an increase in FVC, not to FEV(1)-to-FVC ratio. Among nonresponders, FEV(1), FVC, and RV/TLC did not change after surgery, although recoil pressure increased in both groups. Both groups experienced a reduction in RMC after LVRS. In conclusion, LVRS improves function in emphysema by resizing the lung relative to the chest wall by reducing RV. LVRS does not change airway resistance but decreases RMC, which attenuates the potential benefits of LVRS that are generated by reducing RV/TLC. Among nonresponders, recoil pressure increased out of proportion to reduced volume, such that no increase in vital capacity or improvement in FEV(1) occurred.
   
   
3. Ingenito, E. P., R. L. Berger, et al. (2003). "Bronchoscopic lung volume reduction using tissue engineering principles." Am J Respir Crit Care Med 167(5): 771-8.
   
   Bronchoscopic lung volume reduction (BLVR), a minimally invasive procedure based on tissue engineering principles, was performed in six sheep with papain-induced experimental emphysema (EMPH). Physiologic measurements, at baseline, after generation of EMPH, and at 3 and 9 weeks after BLVR, included lung volumes, diffusing capacity (DL(CO)), pressure-volume relationships for the lung and chest wall, pleural pressures generated during active respiratory muscle contraction, lung resistance and dynamic elastance. The animal model displayed hyperinflation (change in total lung capacity +8%; change in residual volume +66%), reduced DL(CO) (-21%), and elevated airway resistance (+76%) that resembled advanced human EMPH. BLVR was well tolerated without complications, and it reduced lung volumes (change in total lung capacity -16%; change in residual volume -55%) in a pattern that resulted in significant improvements in vital capacity (10%). At autopsy, well-organized, peripheral scars associated with tissue contraction were observed at 33 of the 36 (91%) treated sites. There was no evidence of infection, abscess, or granuloma formation, or allergic reaction. Scar tissue, generated by BLVR, replaced hyperinflated lung, reduced overall lung volume, and improved respiratory function safely and consistently. The BLVR technology employed in this study addresses the limitations identified in our prior attempt at BLVR therapy and appears safe and effective enough to justify a trial in humans.
   
   
4. Hunsaker, A. R. and J. J. Reilly (2003). "Images in clinical medicine. Centrilobular emphysema with predominantly upper-lobe involvement." N Engl J Med 348(21): 2091.
   
   
5. Silverman, E. K., J. D. Mosley, et al. (2002). "Genome-wide linkage analysis of severe, early-onset chronic obstructive pulmonary disease: airflow obstruction and chronic bronchitis phenotypes." Hum Mol Genet 11(6): 623-32.
   
   Familial aggregation of chronic obstructive pulmonary disease (COPD) has been demonstrated, but linkage analysis of COPD-related phenotypes has not been reported previously. An autosomal 10 cM genome-wide scan of short tandem repeat (STR) polymorphic markers was analyzed for linkage to COPD-related phenotypes in 585 members of 72 pedigrees ascertained through severe, early-onset COPD probands without severe alpha1-antitrypsin deficiency. Multipoint non-parametric linkage analysis (using the ALLEGRO program) was performed for qualitative phenotypes including moderate airflow obstruction [forced expiratory volume at one second (FEV(1)) < 60% predicted, FEV(1)/FVC < 90% predicted], mild airflow obstruction (FEV(1) < 80% predicted, FEV(1)/FVC < 90% predicted) and chronic bronchitis. The strongest evidence for linkage in all subjects was observed at chromosomes 12 (LOD = 1.70) and 19 (LOD = 1.54) for moderate airflow obstruction, chromosomes 8 (LOD = 1.36) and 19 (LOD = 1.09) for mild airflow obstruction and chromosomes 19 (LOD = 1.21) and 22 (LOD = 1.37) for chronic bronchitis. Restricting analysis to cigarette smokers only provided increased evidence for linkage of mild airflow obstruction and chronic bronchitis to several genomic regions; for mild airflow obstruction in smokers only, the maximum LOD was 1.64 at chromosome 19, whereas for chronic bronchitis in smokers only, the maximum LOD was 2.08 at chromosome 22. On chromosome 12p, 12 additional STR markers were genotyped, which provided additional support for an airflow obstruction locus in that region with a non-parametric multipoint approach for moderate airflow obstruction (LOD = 2.13) and mild airflow obstruction (LOD = 1.43). Using a dominant model with the STR markers on 12p, two point parametric linkage analysis of all subjects demonstrated a maximum LOD score of 2.09 for moderate airflow obstruction and 2.61 for mild airflow obstruction. In smokers only, the maximum two point LOD score for mild airflow obstruction was 3.14. These observations provide suggestive evidence that there is a locus on chromosome 12p which contributes to susceptibility to early-onset COPD.
   
   
   
6. Silverman, E. K., L. J. Palmer, et al. (2002). "Genomewide linkage analysis of quantitative spirometric phenotypes in severe early-onset chronic obstructive pulmonary disease." Am J Hum Genet 70(5): 1229-39.
   
   Chronic obstructive pulmonary disease (COPD) is a common, complex disease associated with substantial morbidity and mortality. COPD is defined by irreversible airflow obstruction; airflow obstruction is typically determined by reductions in quantitative spirometric indices, including forced expiratory volume at 1 s (FEV(1)) and the ratio of FEV(1) to forced vital capacity (FVC). To identify genetic determinants of quantitative spirometric phenotypes, an autosomal 10-cM genomewide scan of short tandem repeat (STR) polymorphic markers was performed in 72 pedigrees (585 individuals) ascertained through probands with severe early-onset COPD. Multipoint variance-component linkage analysis (using SOLAR) was performed for quantitative phenotypes, including FEV(1), FVC, and FEV(1)/FVC. In the initial genomewide scan, significant evidence for linkage to FEV(1)/FVC was demonstrated on chromosome 2q (LOD score 4.12 at 222 cM). Suggestive evidence was found for linkage to FEV(1)/FVC on chromosomes 1 (LOD score 1.92 at 120 cM) and 17 (LOD score 2.03 at 67 cM) and to FVC on chromosome 1 (LOD score 2.05 at 13 cM). The highest LOD score for FEV(1) in the initial genomewide scan was 1.53, on chromosome 12, at 36 cM. After inclusion of 12 additional STR markers on chromosome 12p, which had been previously genotyped in this population, suggestive evidence for linkage of FEV(1) (LOD score 2.43 at 37 cM) to this region was demonstrated. These observations provide both significant evidence for an early-onset COPD-susceptibility locus on chromosome 2 and suggestive evidence for linkage of spirometry-related phenotypes to several other genomic regions. The significant linkage of FEV(1)/FVC to chromosome 2q could reflect one or more genes influencing the development of airflow obstruction or dysanapsis.
   
   
   
7. Ingenito, E. P., S. H. Loring, et al. (2001). "Comparison of physiological and radiological screening for lung volume reduction surgery." Am J Respir Crit Care Med 163(5): 1068-73.
   
   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).
   
   
   
8. Ingenito, E. P., S. H. Loring, et al. (2001). "Interpreting improvement in expiratory flows after lung volume reduction surgery in terms of flow limitation theory." Am J Respir Crit Care Med 163(5): 1074-80.
   
   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.
   
   
   
9. Reilly, J. J., Jr. (1999). "Evidence-based preoperative evaluation of candidates for thoracotomy." Chest 116(6 Suppl): 474S-476S.
   
   All patients considered for thoracotomy should have preoperative spirometry. Patients meeting the criteria outlined below should also have quantitative radionuclide perfusion scanning. Patients felt to be at high risk on the basis of predicted postoperative FEV1 should be considered for exercise assessment. If exercise assessment is performed, an MVO2 of < 10-15 mL/kg/min or a predicted postoperative MVO2 < 10 mL/kg/min identifies a patient at very high risk for complications and mortality. Limited available data support the use of preoperative risk indices to identify patients at high risk (See Table 4). Lung volume reduction surgery may provide new approaches in selected patients with significant obstructive lung disease and concomitant lung cancer.
   
   
10. Moy, M. L., E. P. Ingenito, et al. (1999). "Health-related quality of life improves following pulmonary rehabilitation and lung volume reduction surgery." Chest 115(2): 383-9.
    
    STUDY OBJECTIVES: To evaluate changes in health-related quality of life (HRQL) as assessed by the Medical Outcomes Study Short Form 36-item questionnaire (SF-36) after pulmonary rehabilitation and lung volume reduction surgery (LVRS). DESIGN: Prospective cohort study. PATIENTS: Nineteen patients with severe emphysema who underwent pulmonary rehabilitation in preparation for LVRS. INTERVENTIONS: Pulmonary rehabilitation followed by bilateral sequential LVRS. MEASUREMENTS AND RESULTS: HRQL assessed by the SF-36 was measured at baseline, after pulmonary rehabilitation, and 6 months after LVRS. One-way analysis of variance with repeated measures demonstrated no significant change from baseline in any of the eight domains after pulmonary rehabilitation. Scores for only one domain, vitality, improved significantly after LVRS compared with scores after pulmonary rehabilitation. However, significant improvements over baseline scores were demonstrated after combined preoperative pulmonary rehabilitation and LVRS in the domains of physical functioning, role limitations due to physical problems, social functioning, and vitality. Pulmonary rehabilitation contributed most to the overall improvements in role limitations due to physical problems, whereas LVRS contributed mainly to the overall improvements in physical functioning, social functioning, and vitality. CONCLUSIONS: Patients with severe emphysema experience significant improvements in both physical and social health status as assessed by the SF-36 after combined pulmonary rehabilitation and LVRS. Each intervention makes unique and complementary contributions to the overall improvements in HRQL.
    
    
11. Moy, M. L., S. H. Loring, et al. (1999). "Causes of allograft dysfunction after single lung transplantation for emphysema: extrinsic restriction versus intrinsic obstruction. Brigham and Women's Hospital Lung Transplantation Group." J Heart Lung Transplant 18(10): 986-93.
    
    BACKGROUND: A subset of patients with emphysema who have undergone single lung transplantation (SLT) may subsequently present with dyspnea, worsening airways obstruction, hypoxemia, and progressive chronic native lung hyperinflation. The leading cause of late allograft dysfunction is bronchiolitis obliterans syndrome (BOS). However, extrinsic restriction manifests with a similar clinical presentation and is an additional mechanism to consider. We describe the use of the inspiratory lung resistance (RLi) to distinguish a decline in respiratory status due predominantly to either extrinsic restriction or BOS. METHODS: We studied five patients who underwent SLT for emphysema between 1992 and 1995, in whom the diagnoses of BOS and extrinsic restriction were subsequently entertained. Forced expiratory volume in 1 second (FEV1), RLi, static lung compliance, elastic recoil pressure at total lung capacity (TLC), and the slope of the maximum flow static recoil (MFSR) plot were measured. RESULTS: All patients had severe airflow obstruction, with mean FEV1 0.98 +/- 0.24 liter (26 +/- 5% predicted), elevated static lung compliance, reduced elastic recoil pressure at TLC, and reduced slope of the MFSR plot. Three patients had "low" RLi (9.3-12.8 cm H20/L/sec). Obstruction was attributed predominantly to extrinsic restriction. These patients underwent lung volume reduction surgery (LVRS) on the native lung; improvements in pulmonary mechanics were observed at 6 months. In contrast, two patients had markedly elevated RLi (17.3 and 17.4 cm H2O/L/sec). Obstruction was attributed predominantly to intrinsic airway disease from BOS that was subsequently documented at autopsy. CONCLUSIONS: The RLi appears to be a useful adjunct to the clinical history in distinguishing a decline in respiratory status due predominantly to either BOS or extrinsic restriction in patients who have undergone SLT for emphysema. Determination of the mechanism of allograft dysfunction may allow the selection of an appropriate subset of patients who would benefit from LVRS.
    
    
12. Loring, S. H., D. E. Leith, et al. (1999). "Model of functional restriction in chronic obstructive pulmonary disease, transplantation, and lung reduction surgery." Am J Respir Crit Care Med 160(3): 821-8.
    
    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.
    
    
    
13. Ingenito, E. P., R. B. Evans, et al. (1998). "Relation between preoperative inspiratory lung resistance and the outcome of lung-volume-reduction surgery for emphysema." N Engl J Med 338(17): 1181-5.
    
    BACKGROUND: Surgery to reduce lung volume has recently been reintroduced to alleviate dyspnea and improve exercise tolerance in selected patients with emphysema. A reliable means of identifying patients who are likely to benefit from this surgery is needed. METHODS: We measured lung resistance during inspiration, static recoil pressure at total lung capacity, static lung compliance, expiratory flow rates, and lung volumes in 29 patients with chronic obstructive lung disease before lung-volume-reduction surgery. The changes in the forced expiratory volume in one second (FEV1) six months after surgery were related to the preoperatively determined physiologic measures. A response to surgery was defined as an increase in the FEV1 of at least 0.2 liter and of at least 12 percent above base-line values. RESULTS: Of the 29 patients, 23 had some improvement in FEV1 including 15 who met the criteria for a response to surgery. Among the variables considered, only preoperative lung resistance during inspiration predicted changes in expiratory flow rates after surgery. Inspiratory lung resistance correlated significantly and inversely with improvement in FEV1 after surgery (r=-0.63, P<0.001). A preoperative criterion of an inspiratory resistance of 10 cm of water per liter per second had a sensitivity of 88 percent (14 of 16 patients) and a specificity of 92 percent (12 of 13 patients) in identifying patients who were likely to have a response to surgery. CONCLUSIONS: Preoperative lung resistance during inspiration appears to be a useful measure for selecting patients with emphysema for lung-volume-reduction surgery.
    
    
14. Hunsaker, A., E. Ingenito, et al. (1998). "Preoperative screening for lung volume reduction surgery: usefulness of combining thin-section CT with physiologic assessment." AJR Am J Roentgenol 170(2): 309-14.
    
    OBJECTIVE: This study was performed to assess the usefulness of preoperative thin-section CT alone and in combination with physiologic measurements in emphysema patients being evaluated for lung volume reduction surgery. SUBJECTS AND METHODS: Six 1-mm collimation sections through the chest were obtained in 20 patients being evaluated for lung volume reduction surgery. Extent and severity of emphysema were assessed by visually scoring the images. CT scores ranged from 0 to 144. Inspiratory resistance was measured in 12 of 20 patients and was also used to discriminate between responders (change in forced expiratory volume in 1 sec, > or = 150 ml after surgery) and nonresponders (change in forced expiratory volume in 1 sec, < 150 ml after surgery). RESULTS: Four of 20 patients with mild emphysema as revealed by thin-section CT (scores of < 50) did not improve lung function after lung volume reduction surgery. Eight of the remaining 16 patients with moderate to severe emphysema as revealed by thin-section CT (scores of > 50) underwent inspiratory resistance measurement. Those seven patients whose inspiratory resistance measurement exceeded 8.5 cm H2O/l per second did not respond favorably to lung volume reduction surgery (change in forced expiratory volume in 1 sec, < 150 ml). The remaining five patients whose inspiratory resistance measurement was less than 8.5 cm H2O/l per second responded favorably to lung volume reduction surgery. Thus, only five of the 20 patients showed improvement in forced expiratory volume in 1 sec after surgery. CONCLUSION: Our data suggest that among patients with moderate to severe emphysema who are being examined for lung volume reduction surgery, the combination of radiologic and physiologic assessment is more accurate for predicting a favorable response to lung volume reduction surgery than radiologic assessment alone. However, in patients with chronic obstructive pulmonary disease by the American Thoracic Society criteria, mild emphysema as revealed on thin-section CT virtually precludes further workup because these patients are unlikely to respond favorably to lung volume reduction surgery.
    
    
15. Haley, K. J., M. E. Sunday, et al. (1998). "Inflammatory cell distribution within and along asthmatic airways." Am J Respir Crit Care Med 158(2): 565-72.
    
    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.
    
    
16. Reilly, J. J., Jr. (1997). "Preoperative and postoperative care of standard and high risk surgical patients." Hematol Oncol Clin North Am 11(3): 449-59.
    
    Much of the clinical teaching concerning preoperative evaluation is based upon clinical observations made several decades ago in patients undergoing thoracotomy for both benign and malignant diseases. More recent experience suggests that many "high risk" patients will tolerate pulmonary parenchymal resection. All patients being considered for surgery should have a complete history and physical examination, chest roentgenogram, and screening spirometry. If this initial evaluation reveals normal or mildly obstructed spirometry and absence of comorbid conditions, then the patient is at low risk and postoperative function may be accurately estimated by simple calculation. For patients with moderate or severe obstruction on spirometry (FEV1 less than 50% to 65% predicted), hilar disease, pleural disease, or prior surgery, quantitative radionuclide lung scanning is indicated to allow accurate calculation of postoperative function. For patients with a PPO FEV1 less than 0.8-1.0 L, additional risk stratification should be done after any preoperative interventions. Typically, this includes a formal or informal assessment of exercise capacity. Patients with severely impaired exercise capabilities are at very high risk for postoperative morbidity and mortality, and nonsurgical therapy should be considered. All active smokers at the time of evaluation should quit 3 to 4 weeks prior to planned surgery. Patients with purulent sputum should be treated with appropriate antibiotics. All patients with obstruction demonstrated on spirometry should be started on inhaled beta agonists, with or without inhaled corticosteroids. Postoperative management should focus on early mobilization. This requires adequate analgesia without excessive sedation. This is most easily achieved with local or regional analgesia techniques. The use of this approach, as well as patient-controlled analgesia, allows early mobilization and results in a short length of hospital stay. It should be recognized that if patients have an uncomplicated recovery and leave the hospital quickly (less than 6 days), postoperative pain will be a significant issue at home. Patients should be discharged with an adequate analgesia plan and an adequate supply of analgesic medications.
    
    
    
17. Massaro, A. F., S. Mehta, et al. (1996). "Elevated nitric oxide concentrations in isolated lower airway gas of asthmatic subjects." Am J Respir Crit Care Med 153(5): 1510-4.
    
    Previous studies have raised the possibility that the measurement of nitric oxide (NO.) concentrations in expired air may represent a noninvasive measure of lower airway inflammation. To address the question of whether the elevated NO. recovered in mixed expired air from asthmatic subjects is a reflection of the pulmonary airway microenvironment or merely nasopharyngeal contamination, mixed expired NO. determinations were performed in five normal and five asthmatic subjects before and after orotracheal intubation (thereby isolating the lower airway gas from ambient air contamination or gas conditioned in the nasopharynx). The mixed expired NO. concentrations determined in patients with asthma were significantly elevated (p < 0.05 or less) above those of normal subjects in both the pre- and postintubation samples. After intubation, mixed expired NO. levels were 4.7 +/- 1.3 ppb and 13.2 +/- 2.0 ppb in normal and asthmatic individuals, respectively; the difference in these values was statistically significant (p < 0.01). Lower airway gas, sampled through the bronchoscope during a breathhold, was found to contain NO. concentrations of 7.0 +/- 1.2 ppb and 40.5 +/- 5.6 ppb at the tracheal carina of normal and asthmatic individuals, respectively. The asthmatic values were significantly (p < 0.01) elevated above those found in normal subjects. These findings indicate that the difference in mixed expired NO. of normal subjects and asthmatics reflects a difference in NO. concentration present in the lower airway.
    
    
18. Reilly, J. J., Jr. (1995). "Benefits of aggressive perioperative management in patients undergoing thoracotomy." Chest 107(6 Suppl): 312S-315S.
    
    With lung resection remaining the cornerstone of curative therapy in patients with lung cancer, aggressive perioperative management continues to play a critical role. This review summarizes the most important factors in successful perioperative management. These include patient selection, with an emphasis on which patient variables and hemodynamic assessments are most useful in determining operability. Postoperative management, in particular, patient-controlled analgesia, and pulmonary toilet, are essential to facilitate early patient mobility and to minimize complications, respectively. Aggressive perioperative management can result in reduced postoperative morbidity and mortality, reduced length of hospital stay and expenditures for complications, and it expands the population that can receive potentially curative therapy.
    
    
    
19. Reilly, J. J., Jr., P. Chen, et al. (1991). "Cigarette smoking induces an elastolytic cysteine proteinase in macrophages distinct from cathepsin L." Am J Physiol 261(2 Pt 1): L41-8.
    
    Degradation of the interstitium of the lung by elastolytic enzymes is thought to be a critical component of the pathogenesis of emphysema. Alveolar macrophages are increased in numbers in cigarette smokers and contain the elastolytic cysteine proteinase cathepsin L. We sought to determine if cigarette smoking induces a change in cathepsin L levels in alveolar macrophages which would, in turn, alter the expression of elastolytic activity. Lysates of smokers' macrophages, assayed at pH 5.50, degraded more than seven times as much [3H]elastin as did lysates from nonsmokers' macrophages (44 +/- 20.8 vs. 6 +/- 1.6 micrograms.10(6) cells-1.24 h-1). Little or no activity was demonstrable at neutral pH. Immunoblots of macrophage lysates demonstrated that smokers' cells contain 3.7 +/- 1.1 times as much 25-kDa cathepsin L antigen as nonsmokers' cells. However, as judged by active site labeling, levels of active cathepsin L in smokers and nonsmokers are indistinguishable, suggesting that most of the 25-kDa antigen found in smokers' macrophages is inactive. Inhibitors of cathepsin L had little effect on lysate elastolytic activity, confirming that an enzyme other than cathepsin L is responsible for the increased elastolytic activity seen in smokers' macrophages. Further experiments demonstrated that this second enzyme(s) has a profile of inhibition indicating that it is a cysteine proteinase with optimal activity at pH 5.50. It is this second elastolytic cysteine proteinase(s) that is induced by exposure to cigarette smoke and is responsible for the sevenfold increase in elastolytic activity found in smokers' macrophage lysates.
    
    
    
20. Chapman, H. A., Jr., J. J. Reilly, Jr., et al. (1990). "Identification of cystatin C, a cysteine proteinase inhibitor, as a major secretory product of human alveolar macrophages in vitro." Am Rev Respir Dis 141(3): 698-705.
    
    The major inhibitor of the cysteine class of proteinases found in human body fluids, such as spinal fluid, milk, and seminal plasma, is cystatin C. In this study we show that human bronchoalveolar fluid also contains cystatin C and examine cystatin C expression by alveolar macrophages in vitro. Immunoprecipitation of extracts of metabolically labeled cells and immunoblotting of cellular extracts and culture media show that cystatin C is synthesized as a 14 (+/- 0.5) kilodalton (kD) protein and that greater than 90% of the protein is released as the 14 kD product into the culture supernatant (26.5 +/- 6.8 ng per 10(6) cells per 24 h). Cystatin C is not one of the most abundant proteins secreted during the first 24 h in vitro, representing approximately 10 to 12% of the total protein released by normal nonsmoker macrophages. Alveolar macrophages obtained from cigarette smokers or nonsmoker macrophages exposed to zymosan in vitro released 10 to 55% less cystatin C than nonsmoker macrophages. We also assayed culture supernatants from macrophages of smokers and nonsmokers for functional cystatin C. Supernatants of nonsmoker macrophages inhibited cathepsin B-like amidolytic activity in a fluorometric assay at pH 5.5. The inhibition was blocked by adsorption with Sepharose-coupled cystatin C antibodies and the inhibitor subsequently recovered from the Sepharose beads. In contrast, supernatants from smoker macrophages had obvious cathepsin B-like activity.(ABSTRACT TRUNCATED AT 250 WORDS)
    
    
    
21. Reilly, J. J., Jr., R. W. Mason, et al. (1989). "Synthesis and processing of cathepsin L, an elastase, by human alveolar macrophages." Biochem J 257(2): 493-8.
    
    Cathepsin L was partially purified from lysates of freshly isolated macrophages lavaged from lungs of apparently healthy adults and found to be chromatographically and catalytically identical with liver cathepsin L. Western-blotting analysis showed that lung macrophages contain significant levels of a precursor of cathepsin L (43 kDa) in addition to mature enzyme (25 kDa). After culturing for a further 24 h, the precursor disappeared and a new band, corresponding to 34 kDa, appeared, suggesting that the precursor had been processed to an intermediate form of cathepsin L. Biosynthetic labelling of macrophages in vitro with [35S]methionine followed by immunoprecipitation with the cathepsin L antibody confirmed that the cells synthesize cathepsin L as a 43 kDa precursor that is then processed to the mature form (25 kDa) via a 34 kDa intermediate. The precursor, but not the processed forms, was released into the culture medium. During culture in vitro the 34 kDa intermediate accumulated, and little enzyme was processed to the 24 kDa form, consistent with the immunoblot data. Human lung macrophages contain a 1.5 kb transcript of cathepsin L mRNA, whereas none is detectable in human monocytes. These results establish that differentiation of human macrophages within the lung is accompanied by synthesis and expression of an elastinolytic enzyme, cathepsin L. The altered processing of cathepsin L observed during cultivation in vitro suggests caution in the assessment of the elastinolytic potential of human macrophages based on assay in vitro.
    
    
22. Reilly, J. J. and H. A. Chapman, Jr. (1988). "Association between alveolar macrophage plasminogen activator activity and indices of lung function in young cigarette smokers." Am Rev Respir Dis 138(6): 1422-8.
    
    Recent evidence suggests that connective tissue breakdown in the human lung leading to airway obstruction and emphysema involves proteinases expressed by neutrophils and macrophages that traffic to the lungs in response to cigarette smoke. It remains unclear why only a small fraction of all cigarette smokers develop symptomatic airway obstruction. In this study, we examined indexes of inflammation and proteolytic activity in samples of bronchoalveolar lavage from young cigarette smokers and questioned whether there was any correlation between the extent of inflammation or enzymatic activity and lung function. A total of 125 apparently healthy community volunteers who currently smoked at least one pack per day were evaluated by spirometry. Seven subjects with a relatively low FEV1/FVC (% predicted) were identified and further studied by bronchoalveolar lavage. These were compared with a group of 10 smokers of similar age (mean age, 33 yr) and pack-years and higher FEV1/FVC (% predicted). Both groups showed increased accumulation of lung macrophages and neutrophils as compared to nonsmokers, but there were no differences in total cells or cellular differentials between the groups. Similarly, there were no differences in either alveolar fluid phase elastase, antielastase, and plasminogen activator (PA) activities or macrophage elastolytic activity between the groups. In contrast, there was a clear difference in macrophage plasminogen activator activity between the groups, cells from the group with a lower FEV1/FVC (% predicted) having a higher PA activity than that of macrophages from the group with higher FEV1/FVC (% predicted), i.e., 0.50 +/- 0.16 international urokinase units/10(6) cells versus 0.30 +/- 0.10 units/10(6) cells (p less than 0.0007).(ABSTRACT TRUNCATED AT 250 WORDS)
    
    
    
23. Chapman, H. A., Jr., P. Bertozzi, et al. (1988). "Role of enzymes mediating thrombosis and thrombolysis in lung disease." Chest 93(6): 1256-63.
    
    Enzymes of the blood coagulation and fibrinolytic cascades are prominent in both the vascular and alveolar compartments of the human lung. Important differences exist in the regulation of these enzyme activities between the vascular and the alveolar compartments, suggesting different functions of similar enzymes in the two compartments. In the vascular bed, endothelial cells provide a nonthrombogenic lining layer and release small amounts of tissue plasminogen activator into the circulation, maintaining patency of the vascular bed, whereas the alveolar epithelial surface is replete with active enzymes of the extrinsic pathway of coagulation as well as urokinase. The alveolar surface seems primed to localize and degrade any fibrin that has leaked into alveoli during hemorrhagic states. In addition, parenchymal lung cells such as resident macrophages are coated with urokinase, providing a mechanism for cellular migration and ongoing extracellular matrix metabolism. Amplification of the PA/plasmin system in the lung during chronic inflammation, eg, cigarette smoking, could accelerate connective tissue breakdown. Recent evidence indicates that in acute inflammation there is an enhancement of mediators of coagulation and suppression of fibrinolysis. These observations may partly explain prior pathologic observations regarding the deposition of hyaline membranes and persistence of alveolar fibrin/fibronectin deposits that may be stimulants for alveolar fibrosis. The assembly of clotting components on the surface of macrophages and the integral involvement of macrophages with fibrin deposits in the lung are likely mechanisms for macrophage immobilization and focal accumulation important to local clearance, host defense, effective chemotactic signalling, and possibly proliferation since thrombin has mitogenic properties for other lung cells. Newer methods focusing on the biology and biochemistry of the pulmonary architecture and its cellular components should further elucidate the importance of these pathways and suggest new therapeutic options.
    
    
    
24. Wilson, D. O., R. M. Rogers, et al. (1986). "Nutritional intervention in malnourished patients with emphysema." Am Rev Respir Dis 134(4): 672-7.
    
    We have previously reported the association of significant malnutrition with pulmonary emphysema and noted that the degree of malnutrition correlated with some measures of pulmonary function. The purpose of this study was to examine the energy requirements of malnourished patients with emphysema and acute effects of nutritional repletion on indices of pulmonary function and nutrition. We studied 6 malnourished patients with emphysema during a 3-wk admission to a clinical research unit. Initially, patients were allowed access to standard food sources ad libitum. Subsequently, if caloric goals were not met, nutritional supplementation was given orally. All patients receiving the ad libitum diet ingested calories in excess of their maintenance energy requirements. All patients increased their body weight (p less than 0.001) and percent ideal body weight (p less than 0.001). Anthropometric nutritional parameters showed a small but significant improvement (p less than 0.05). Although there was no significant change in spirometric results, lung volumes or DLCO after 3 wk maximal inspiratory mouth and transdiaphragmatic pressures increased (p less than 0.005). Peripheral skeletal muscle strength as measured by handgrip also improved (p less than 0.001). We conclude that inability to ingest an adequate number of calories was not the cause of weight loss in these patients. We also found that when given sufficient calories in excess of their needs, patients gain weight. Weight gain and improvement in anthropometric measurements are accompanied by significant improvement in ventilatory and peripheral muscle strength.