Joel D. Cooper

University of Pennsylvania, Filadelfia, Pennsylvania, United States

Are you Joel D. Cooper?

Claim your profile

Publications (170)764.76 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Chronic lung allograft dysfunction (CLAD) remains the major barrier to long-term success after lung transplantation. This report compares gross and microscopic features of lungs removed from patients receiving a redo-transplant as treatment for CLAD.Lungs donated by patients with either the bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS) phenotype of CLAD and appropriate control lungs (eight per group) were air-inflated, frozen solid and kept frozen while a multi-detector computed tomography (MDCT) was obtained. The lung was then cut into 2-cm thick transverse slices and sampled for micro-CT and histopathology.The MDCT showed reduced lung volume with increased lung weight and density in RAS versus BOS and control (p<0.05). Although pre-terminal bronchioles were obstructed in both phenotypes, RAS lungs showed a reduction of pre-terminal bronchioles (p<0.01). Micro-CT and matched histopathology showed that RAS was associated with reduced numbers of terminal bronchioles/lung compared to BOS and controls (p<0.01), with expansion of the interstitial compartment and obliteration of the alveolar airspaces by fibrous connective tissue.RAS is associated with greater destruction of both pre-terminal and terminal bronchioles. Additionally, the interstitial compartments are expanded and alveolar airspaces are obliterated by accumulation of fibrous connective tissue. Copyright ©ERS 2015.
    European Respiratory Journal 06/2015; DOI:10.1183/09031936.00010615 · 7.13 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Lung is a complex gas exchanger with interfacial area (where the gas exchange takes place) is about the size of a tennis court. Respiratory function is linked to the biomechanical stability of the gas exchange or alveolar regions which directly depends on the spatial distributions of the extracellular matrix fibers such fibrillar collagens and elastin fibers. It is very important to visualize and quantify these fibers at their native and inflated conditions to have correct morphometric information on differences between control and diseased states. This can be only achieved in the ex vivo states by imaging directly frozen lung specimens inflated to total lung capacity. Multiphoton microscopy, which uses ultra-short infrared laser pulses as the excitation source, produces multiphoton excitation fluorescence (MPEF) signals from endogenously fluorescent proteins (e.g. elastin) and induces specific second harmonic generation (SHG) signals from non-centrosymmetric proteins such as fibrillar collagens in fresh human lung tissues [J. Struct. Biol. (2010)171,189-196]. Here we report for the first time 3D image data obtained directly from thick frozen inflated lung specimens (~0.7- 1.0 millimeter thick) visualized at -60°C without prior fixation or staining in healthy and diseased states. Lung specimens donated for transplantation and released for research when no appropriate recipient was identified served as controls, and diseased lung specimens donated for research by patients receiving lung transplantation for very severe COPD (n=4) were prepared as previously described [N. Engl. J. Med. (2011) 201, 1567]. Lung slices evenly spaced between apex and base were examined using multiphoton microscopy while maintained at -60°C using a temperature controlled cold stage with a temperature resolution of 0.1°C. Infrared femto-second laser pulses tuned to 880nm, dry microscopic objectives, and non-de-scanned detectors/spectrophotometer located in the reflection geometry were used for generating the 3D images/spectral information. We found that this novel imaging approach can provide spatially resolved 3D images with spectral specificities from frozen inflated lungs that are sensitive enough to identity the micro-structural details of fibrillar collagens and elastin fibers in alveolar walls in both healthy and diseased tissues.
    Proceedings of SPIE - The International Society for Optical Engineering 02/2013; DOI:10.1117/12.2002593 · 0.20 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease consisting of emphysema, small airway obstruction, and/or chronic bronchitis that results in significant loss of lung function over time. METHODS: In order to gain insights into the molecular pathways underlying progression of emphysema and explore computational strategies for identifying COPD therapeutics, we profiled gene expression in lung tissue samples obtained from regions within the same lung with varying amounts of emphysematous destruction from smokers with COPD (8 regions x 8 lungs = 64 samples). Regional emphysema severity was quantified in each tissue sample using the mean linear intercept (Lm) between alveolar walls from micro-CT scans. RESULTS: We identified 127 genes whose expression levels were significantly associated with regional emphysema severity while controlling for gene expression differences between individuals. Genes increasing in expression with increasing emphysematous destruction included those involved in inflammation, such as the B-cell receptor signaling pathway, while genes decreasing in expression were enriched in tissue repair processes, including the transforming growth factor beta (TGF beta) pathway, actin organization, and integrin signaling. We found concordant differential expression of these emphysema severity-associated genes in four cross-sectional studies of COPD. Using the Connectivity Map, we identified GHK as a compound that can reverse the gene-expression signature associated with emphysematous destruction and induce expression patterns consistent with TGF beta pathway activation. Treatment of human fibroblasts with GHK recapitulated TGF beta-induced gene-expression patterns, led to the organization of the actin cytoskeleton, and elevated the expression of integrin beta1. Furthermore, addition of GHK or TGF beta restored collagen I contraction and remodeling by fibroblasts derived from COPD lungs compared to fibroblasts from former smokers without COPD. CONCLUSIONS: These results demonstrate that gene-expression changes associated with regional emphysema severity within an individual¿s lung can provide insights into emphysema pathogenesis and identify novel therapeutic opportunities for this deadly disease. They also suggest the need for additional studies to examine the mechanisms by which TGF beta and GHK each reverse the gene-expression signature of emphysematous destruction and the effects of this reversal on disease progression.
    Genome Medicine 08/2012; 4(8):67. DOI:10.1186/gm368 · 4.94 Impact Factor
  • American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California; 05/2012
  • American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California; 05/2012
  • [Show abstract] [Hide abstract]
    ABSTRACT: Adenoid cystic carcinoma is a rare malignancy that usually originates in the salivary glands of the head and neck but has rarely been known to originate in the trachea. This histology has a predilection for perineural invasion and a tendency for both local and distant recurrences. While surgical resection is the mainstay of treatment of tracheal adenoid cystic carcinoma, tumor size, location, and patient comorbidities may preclude surgery, and the optimal nonsurgical management remains undefined. In the absence of locoregional lymph node metastases, we recommend highly conformal radiotherapy alone to a dose of 80 Gy. We report on two patients with unresectable disease who were treated with definitive radiotherapy: one using conventional photons and one treated with a combination of photon and proton beams. Both patients were treated to a dose of 80 Gy with acceptable toxicities and objective clinical and radiographic response. The patient treated with conventional photons has no evidence of recurrent disease at 5 years; the patient treated with protons has continued evidence of response without evidence of disease recurrence 11 months after treatment.
    Chest 05/2012; 141(5):1323-6. DOI:10.1378/chest.11-0925 · 7.13 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The major sites of obstruction in chronic obstructive pulmonary disease (COPD) are small airways (<2 mm in diameter). We wanted to determine whether there was a relationship between small-airway obstruction and emphysematous destruction in COPD. We used multidetector computed tomography (CT) to compare the number of airways measuring 2.0 to 2.5 mm in 78 patients who had various stages of COPD, as judged by scoring on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) scale, in isolated lungs removed from patients with COPD who underwent lung transplantation, and in donor (control) lungs. MicroCT was used to measure the extent of emphysema (mean linear intercept), the number of terminal bronchioles per milliliter of lung volume, and the minimum diameters and cross-sectional areas of terminal bronchioles. On multidetector CT, in samples from patients with COPD, as compared with control samples, the number of airways measuring 2.0 to 2.5 mm in diameter was reduced in patients with GOLD stage 1 disease (P=0.001), GOLD stage 2 disease (P=0.02), and GOLD stage 3 or 4 disease (P<0.001). MicroCT of isolated samples of lungs removed from patients with GOLD stage 4 disease showed a reduction of 81 to 99.7% in the total cross-sectional area of terminal bronchioles and a reduction of 72 to 89% in the number of terminal bronchioles (P<0.001). A comparison of the number of terminal bronchioles and dimensions at different levels of emphysematous destruction (i.e., an increasing value for the mean linear intercept) showed that the narrowing and loss of terminal bronchioles preceded emphysematous destruction in COPD (P<0.001). These results show that narrowing and disappearance of small conducting airways before the onset of emphysematous destruction can explain the increased peripheral airway resistance reported in COPD. (Funded by the National Heart, Lung, and Blood Institute and others.).
    New England Journal of Medicine 10/2011; 365(17):1567-75. DOI:10.1056/NEJMoa1106955 · 54.42 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The clinical benefit of postoperative mediastinal radiation for completely resected Masaoka stage 2 thymoma remains controversial. Due to its indolent nature and infrequent recurrences, no study has definitively determined the optimal approach. We retrospectively reviewed 175 consecutive patients who underwent thymic resection from January 1990 to July 2008 at the University of Pennsylvania. The primary endpoint was local recurrence, defined as recurrence within the surgical bed, treated by resection alone versus resection plus radiation. Patients with high recurrence risk were referred for adjuvant radiotherapy. Seventy-four Masaoka stage 2 patients were resected; 62 underwent complete resections with adequate postsurgical follow-up. Thirty-seven patients received adjuvant radiotherapy and 25 patients were observed. The median radiation dose was 5040 cGy. The median follow-up for all patients was 52 months. The local recurrence rate was 3.2%. The proportion of recurrences in patients observed after surgery was 8% versus 0% in those who received adjuvant radiotherapy (P = .15). Size was not an independent predictor of recurrence (P = .81). The tumor-related death rate was 0%, and overall death rate was 3.2%. One death occurred in each group, observation, and radiation. There were no grade 3 or 4 complications with radiation. Recurrence rates were low following resection of stage 2 thymoma either with or without adjuvant radiotherapy. Adjuvant radiotherapy, although well-tolerated, did not significantly decrease the local relapse rate. Differences may be observed in future studies of patients who are at higher risk for local recurrence, based on completeness of resection, World Health Organization histology, and tumor size.
    Cancer 08/2011; 117(15):3502-8. DOI:10.1002/cncr.25851 · 4.90 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Tracheobronchopathia osteochondroplastica is a rare, benign disorder of upper airways characterized by multiple submucosal metaplastic cartilaginous and bony nodules arising from the tracheal cartilage. We report an unusual presentation of tracheobronchopathia osteochondroplastica as a single dominant nodule arising from the anterior tracheal rings in a young adult man who presented with wheezing and symptoms of airway obstruction. The differential diagnosis of cartilaginous and bony endotracheal lesions is discussed.
    Annals of diagnostic pathology 07/2011; 15(6):431-5. DOI:10.1016/j.anndiagpath.2011.04.009 · 1.11 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Rationale: To gain insights into molecular processes that contribute to airway-wall thickening and alveolar destruction in COPD, and the relationship between these two processes, we microdissected airway and parenchyma from resected lungs obtained from individuals undergoing lung transplantation for severe COPD to identify gene expression differences between lung regions exhibiting increasingly severe airway and parenchymal COPD pathologies. We used this data to identify pathways altered with progressive airway thickening and/or emphysematous destruction in both airway and parenchymal tissue. Methods: Explanted lungs from six GOLD 4 and two control patients were inflated with air, rapidly frozen in liquid N fumes, examined by 2 HRCT, and cut into 2 cm thick transverse slices. Frozen tissue cores (8 cores/lung) were removed and scanned using micro-CT to quantify the severity of emphysematous destruction (Lm). Airway thickness (AT) was quantified using H&E stained frozen sections. Cores were subdivided into airway and parenchymal components using laser capture microdissection. mRNA was extracted separately from the laser-captured airway and from the adjacent parenchyma, analyzed using Affymetrix GeneST microarrays, and associated with Lm and AT using a linear mixed-effects model. Results: In the airway, differential expression of genes related to cell adhesion, immune, and inflammatory processes was associated with AT. In the parenchyma, differential expression of genes related to apoptosis, immune, and inflammatory processes was associated with Lm. Also in the parenchyma, several pathways identified in animal models of emphysema were associated with Lm and several others with adjacent AT. In both the airway and parenchyma differential expression of genes related to the TGF-beta signaling pathway was associated with AT. Conclusions: This is the first study to identify the genomic alterations associated with these distinct sub-phenotypes of COPD, which may have implications for targeted therapy, and it highlights the complex interplay between processes related to COPD pathogenesis occurring in both the airway and lung parenchyma.
  • American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado; 05/2011
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Airway Bypass is a catheter-based, bronchoscopic procedure in which new passageways are created that bypass the collapsed airways, enabling trapped air to exit the lungs. The Exhale Airway Stents for Emphysema (EASE) Trial was designed to investigate whether Exhale® Drug-Eluting Stents, placed in new passageways in the lungs, can improve pulmonary function and reduce breathlessness in severely hyperinflated, homogeneous emphysema patients (NCT00391612). The multi-center, randomized, double-blind, sham-controlled trial design was posted on http://www.clinicaltrials.gov in October 2006. Because Bayesian statistics are used for the analysis, the proposed enrollment ranged from 225 up to 450 subjects at up to 45 institutions. Inclusion criteria are: high resolution CT scan with evidence of homogeneous emphysema, post-bronchodilator pulmonary function tests showing: a ratio of FEV1/FVC < 70%, FEV1 ≤ 50% of predicted or FEV1 < 1 liter, RV/TLC ≥ 0.65 at screening, marked dyspnea score ≥ 2 on the modified Medical Research Council scale of 0-4, a smoking history of at least 20 pack years and stopped smoking for at least 8 weeks prior to enrollment. Following 16 to 20 supervised pulmonary rehabilitation sessions, subjects were randomized 2:1 to receive either a treatment (Exhale® Drug-Eluting Stent) or a sham bronchoscopy. A responder analysis will evaluate the co-primary endpoints of an FVC improvement ≥ 12% of the patient baseline value and modified Medical Research Council dyspnea scale improvement (reduction) ≥ 1 point at the 6-month follow-up visit. If through the EASE Trial, Airway Bypass is shown to improve pulmonary function and reduce dyspnea while demonstrating an acceptable safety profile, then homogeneous patients will have a minimally invasive treatment option with meaningful clinical benefit. ClinicalTrials.gov: NCT00391612.
    BMC Pulmonary Medicine 01/2011; 11:1. DOI:10.1186/1471-2466-11-1 · 2.49 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSE Preliminary studies based on micro-CT suggest that there is a significant reduction in the number of terminal bronchioles (TB) in COPD lungs even in areas without pathological evidence of emphysema (McDonough et al ATS 2009). Therefore, estimating the number of airways can help detect disease burden at an early stage of COPD. Because the radiation dose required for micro-CT is too toxic for human tissue, the purpose of this study was to investigate whether the application of stereological principles to analyze thin section CT, an existing technology that can be used on humans in vivo, can provide a valid approach to estimate the number of airways. METHOD AND MATERIALS Frozen lung specimens from 6 COPD patients and 4 donors were scanned using a thin section CT scanner with 1mm slice thickness. Lung specimens were subsequently cut into 2 cm thick slices in the plane of the CT scan and 20 tissue cores per lung were taken for micro-CT imaging. Approximately 1000 contiguous micro-CT images per tissue core were examined to identify TB by following conducting airways to where they branched into respiratory bronchioles. The total count was divided by the volume of the tissue core to give TB/ml. The CT images were separately examined using a stereology-based dissector method; where a pair of the “inclusion” and “exclusion” planes separated by 3mm distance defined a volume of tissue. Airways only appearing on “inclusion” planes but not on “exclusion” planes were counted. Thirty pairs of CT images were examined per lung. The total count was divided by the volume of the dissector to give airway/ml. The correlation between TB/ml and airway/ml was tested using spearman correlation. RESULTS The number of airways was reduced in 6 COPD lungs as compared to 4 donors (mean TB/ml: 1.39 vs. 6.84, p=0.002; mean airway/ml: 0.12 vs. 0.25, p=0.029). The correlation between TB/ml from micro-CT and airway/ml from CT-dissector was significant (r=0.7, p=0.024). CONCLUSION The combination of stereology-based dissector principle and thin section CT provides a valid method capable of estimating the number of airway in human lungs in vivo. CLINICAL RELEVANCE/APPLICATION This method allows the important small airway abnormality to be diagnosed at an early stage of COPD in vivo and to be used as an outcome measure for new therapies designed to prevent this condition.
    Radiological Society of North America 2010 Scientific Assembly and Annual Meeting; 11/2010
  • Joel D Cooper
    The Journal of thoracic and cardiovascular surgery 10/2010; 140(4):743-6. DOI:10.1016/j.jtcvs.2010.06.037 · 3.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate the use of inflation-fixed lung tissue for emphysema quantification with computed tomography (CT) and He magnetic resonance (MR) diffusion imaging. Fourteen subjects representing a range of chronic obstructive pulmonary disease severity who underwent complete or lobar lung resection were studied. Computed tomographic measurements of lung attenuation and MR measurements of the hyperpolarized 3He apparent diffusion coefficient (ADC) in resected specimens fixed in inflation with heated formalin vapor were compared with measurements obtained before fixation. The mean (SD) CT emphysema indices were 56% (17%) before and 58% (19%) after fixation (P = 0.77; R = 0.76). Index differences correlated with differences in lung volume (R = 0.47). The mean (SD) 3He ADCs were 0.40 (0.15) cm/s before and 0.39 (0.14) cm/s after fixation (P = 0.03, R = 0.98). The CT emphysema index and the 3He ADC were correlated before (R = 0.89) and after fixation (R = 0.79). Concordance of CT and 3He MR imaging measurements in unfixed and inflation-fixed lungs supports the use of inflation-fixed lungs for quantitative imaging studies in emphysema.
    Journal of computer assisted tomography 08/2010; 34(5):773-9. DOI:10.1097/RCT.0b013e3181e480f9 · 1.60 Impact Factor
  • Joel D Cooper
    Chest 08/2010; 138(2):243-5. DOI:10.1378/chest.10-0829 · 7.13 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Rationale: To quantify the number of alveoli in the human lung. Methods: Explanted lungs from unused donor lungs (n=4) were collected. These lungs were inflated to TLC with air and frozen solid by suspending them in liquid nitrogen vapor. Each lung was cut into 2 cm-thick slices in the plane of preoperative CT scan and a core of frozen tissue approximately 1 cm in diameter and 2 cm in length were removed from each slice and processed for micro-CT examination. The number of alveoli was quantified on 5 cores distributed from the apex to base of each lung. For each core an optical dissector was used on 5 random regions of interest wherein the number of alveolar openings were counted. Results: The number of alveoli /mm of lung tissue averaged 27.5±2.2 alveoli /mm (mean ± std.error) and range of 3 3 16.9-40.0 (min-max) in the 20 cores examined. Variation in alveolar density appears to be due to increase in alveolar ducts in lower density regions. Calculating total number of alveoli within a single lung shows total number of alveoli averaged 80±10x10 and range of 6 68-111x10 . Number of alveoli per terminal bronchiole (TB) (McDonough 2009) averaged 3932±747 alveoli /TB and ranged from 6 2264-5617. Examining alveolar density by lung height shows a correlation of increased number of alveoli near the apex of the lung compared to the base. Conclusion: Variation in alveolar density occurs in normal human lungs with an increased number of alveoli present in the apex of the lung compared to the base.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Corresponding author's email: Masaru.Suzuki@hli.ubc.ca : The inflammatory response underlies the pathogenesis of emphysema but the quantitative relationship between the RATIONALE accumulation of inflammatory cells and emphysematous tissue destruction is under-investigated. : To quantify the association PURPOSE between alveolar inflammatory cell infiltration, the severity of emphysematous destruction and terminal bronchiolar number in COPD. : Explanted unilateral lungs from 6 GOLD 4 COPD patients (4 with centrilobular emphysematous phenotype, 1 with METHODS alpha1-antitrypsin deficiency, and 1 with small airway obstructive phenotype) and 2 donors (control) were inflated to total lung capacity and frozen in liquid N vapor. Each specimen was then cut into 2 cm thick slices and 8 cores of tissue per lung were removed, fixed at 2 -80°C, dried and micro-CT scanned to measure the degree of emphysema (mean linear intercept (Lm), alveolar surface area (SA)) and number of terminal bronchioles in each core. Companion frozen tissue cores cut immediately adjacent to those used for micro-CT were vacuum embedded in 50% OCT and refrozen on dry ice. Volume fraction (Vv) of neutrophils, macrophages, eosinophils, CD4 cells, CD8 cells, B cells, and NK cells in alveolar tissue of each core was determined by point counting specifically stained frozen tissue sections cut from these frozen tissue cores. : The analysis of all 8 cases (64 cores) showed that progression of emphysema (decrease of SA) RESULTS was correlated with Vv values of macrophages (p<0.0001), CD4 cells (p<0.0001), CD8 cells (p=0.03), and B cells (p<0.0001). On the other hand, Vv values of CD8 cells (p=0.004) and NK cells (p=0.01) in alveolar tissue were increased in mild emphysema (600<Lm<1,000 µm) compared to non-emphysematous regions (Lm<600 µm), but not in severe emphysema (Lm>1,000 µm). Analysis of the centrilobular emphysematous phenotype subgroup (4 cases, 32 cores) showed that Vv values of macrophages (p<0.0001), CD4 cells (p=0.02), and B cells (p=0.006) in alveolar tissue were related to emphysema severity, whereas there was no association between any alveolar tissue inflammatory cell type and number of terminal bronchioles/ml of tissue core. : The severity of emphysematous destruction CONCLUSION is associated with an amplified alveolar tissue infiltration by macrophages, CD4 cells, and B cells, consistent with an inflammatory immune response.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Corresponding author's email: Masaru.Suzuki@hli.ubc.ca : Abnormal collagen accumulation may be part a defective repair process in COPD. : To quantify total collagen, RATIONALE PURPOSE collagen I and collagen III accumulation in relations to total number of bronchioles, thickening of the remaining bronchiolar walls and emphysematous destruction in COPD. : Individual explanted lungs from 6 patients with GOLD 4 COPD and 2 donor (control) METHODS lungs were inflated to total lung capacity, rapidly frozen in liquid N vapor and cut into 2 cm thick slices. One frozen core of tissue 2 removed from each of 8 slices of lung was fixed in a mixture of 1% glutaraldehyde in acetone at -80°C, dried and micro-CT scanned to measure the degree of emphysema (alveolar surface area) and number of terminal bronchioles in each core. Companion frozen tissue cores cut immediately adjacent to those used for micro-CT, vacuum embedded in 50% OCT and refrozen on dry ice. Volume fractions (Vv) of total collagen, collagen I and III were measured in both small airway walls and alveolar tissue using color segmentation of specifically stained whole mount sections from these frozen tissue cores. Small airway wall thickness was measured with H&E stained sections. : Vv of total collagen in alveolar tissue correlated with the number of terminal bronchioles (p=0.01) but not with progression of RESULTS emphysematous destruction. In contrast, Vv of collagen I and the ratio of collagen I to III in alveolar tissue correlated with progression of emphysema (p<0.0001, p=0.01, respectively) and decreased number of terminal bronchioles (p<0.0001, p=0.0005, respectively). The Vv of total collagen and Vv of collagen III in small airway walls were negatively correlated with small airway wall thickness (p=0.0004, p=0.01, respectively) and positively correlated with number of terminal bronchioles (p=0.0008, p=0.01, respectively), and the ratio of collagen I to III was correlated with small airway wall thickness (p=0.004) and decreased number of terminal bronchioles (p=0.004). : CONCLUSION Emphysematous destruction and thickened small airway wall are associated with relative increase in accumulation of type I collagen, and decrease in number of terminal bronchioles is associated with decreased total collagen accumulation and a relative increase in type I collagen accumulation in both of alveolar and small airway wall tissue.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To gain insights into the pathogenesis of chronic obstructive pulmonary disease (COPD), we profiled gene expression in Introduction: regions with differing emphysema severity from six lungs with COPD and two donor lungs. Regional emphysema severity was Methods: determined using micro-CT and quantified as the mean linear intercept between alveolar septa (Lm). One μg of RNA was isolated from eight samples from each of eight lungs (8 x 8 = 64 total samples), processed, and hybridized onto the Affymetrix Human Exon 1.0 ST array. The Robust Multichip Average (RMA) algorithm was used to generate transcript-level expression values for 17881 genes. Differential expression was determined by linear mixed effect models that accounts for inter-individual differences in baseline gene-expression. One-hundred and twenty-seven genes had expression profiles significantly correlated with the degree of emphysema (FDR Results: q-value < 0.1). These genes are significantly enriched for those previously found to have COPD and/or COPD-severity associated expression profiles in cross-sectional studies that compared lung tissue from individuals with and without COPD. Gene set enrichment analysis demonstrated that the genes that decrease with increasing regional emphysema severity are enriched for genes with roles in cellular structure, integrin signaling, extracellular matrix, and focal adhesion as well as genes in the VEGF and TGFβ pathways, which are known to be involved in angiogenesis and extracellular matrix (ECM) remodeling, respectively. Genes induced by TGFβ1 in several publically available gene expression datasets were found to be enriched among the downregulated genes further implicating the TGFβ pathway in COPD pathogenesis. Immunohistochemistry showed that SMAD6, a member of the TGFβ family, is downregulated in endothelial cells in the lung vasculature. The Context Likelihood of Related (CLR) algorithm was used to infer a gene co-expression network in order to elucidate which transcription factors may be playing a role in emphysema progression. The Ingenuity Pathway Analysis (IPA) tool showed that genes connected to EPAS1 (HIF2-alpha) in the CLR network including KDR (VEGFR2) and TEK (TIE2) had supporting experimental evidence for transcriptional regulation. EPAS1 is a hypoxia inducible factor that was downregulated in regions of severe emphysema. We have identified gene expression patterns that correlate with the progression of emphysema. Our Conclusion: hope is that understanding the processes that promote emphysematous destruction of the alveolae will lead to a better understanding of the mechanisms responsible for COPD progression, as well as suggest targets for future development of more effective anti-COPD therapies.

Publication Stats

6k Citations
764.76 Total Impact Points

Institutions

  • 2006–2015
    • University of Pennsylvania
      • • Department of Medicine
      • • Division of Cardiothoracic Surgery
      Filadelfia, Pennsylvania, United States
  • 2012
    • William Penn University
      Filadelfia, Pennsylvania, United States
  • 2011
    • St. Paul's Hospital
      Saskatoon, Saskatchewan, Canada
  • 2007–2009
    • Hospital of the University of Pennsylvania
      • Division of Cardiothoracic Surgery
      Philadelphia, Pennsylvania, United States
  • 1991–2009
    • Washington University in St. Louis
      • • Department of Surgery
      • • Department of Physics
      • • Division of Cardiothoracic Surgery
      • • Division of Pulmonary and Critical Care
      San Luis, Missouri, United States
  • 1993–2006
    • Barnes Jewish Hospital
      San Luis, Missouri, United States
  • 2003
    • Sapienza University of Rome
      Roma, Latium, Italy
  • 1995
    • University of New Mexico Hospitals
      Albuquerque, New Mexico, United States
  • 1988–1993
    • University of Toronto
      • • Department of Surgery
      • • Faculty of Medicine
      Toronto, Ontario, Canada