<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03034642</url>
  </required_header>
  <id_info>
    <org_study_id>VAAAHS Curtis 0038</org_study_id>
    <secondary_id>I01CX000911</secondary_id>
    <nct_id>NCT03034642</nct_id>
  </id_info>
  <brief_title>Modulation of Steroid Immunosuppression by Alveolar Efferocytosis</brief_title>
  <official_title>Modulation of Steroid Immunosuppression by Alveolar Efferocytosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>VA Ann Arbor Healthcare System</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Michigan</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>VA Ann Arbor Healthcare System</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The long-term goals of this study are (a) to understand the biological underpinnings for the&#xD;
      increased incidence of community-acquired pneumonia in patients with chronic obstructive&#xD;
      pulmonary disease (COPD) who are treated with inhaled corticosteroids; and (b) to develop&#xD;
      novel therapies to treated this problem using over-expression of micro-RNAs (miRNAs).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Treating chronic obstructive pulmonary disease (COPD) patients with inhaled&#xD;
      glucocorticosteroids has been convincingly shown to increase their risk of pneumonia, but the&#xD;
      responsible mechanisms are undefined. Work from this laboratory suggests a possible&#xD;
      mechanism, related to the increased numbers of cells dying by apoptosis in the lungs in COPD,&#xD;
      especially in emphysema. Uptake of apoptotic cells (&quot;efferocytosis&quot;) suppresses the ability&#xD;
      of alveolar macrophages (AM) to fight infections. By markedly increasing AM efferocytosis,&#xD;
      glucocorticoids plus apoptotic cells cause greater immune defects than either stimulus alone.&#xD;
      These defects include reductions in killing of Streptococcus pneumoniae by human AM and&#xD;
      murine AM in vitro, and in clearance of viable pneumococci from lungs of mice. This effect is&#xD;
      called glucocorticoid augmented efferocytosis (GCAE). MicroRNAs (miRNAs) are 19-25&#xD;
      nucleotide-long non-coding RNAs that coordinately target large numbers of genes and reduce&#xD;
      their protein products. Preliminary data imply that defective AM function is caused by&#xD;
      down-regulation of specific miRNAs by GCAE (but not by apoptotic cells alone or&#xD;
      glucocorticosteroids alone). The long-term goal of this project is to develop novel&#xD;
      inhalational treatments based on transient over-expression of these specifically decreased&#xD;
      miRNAs, to reverse defective AM immune function when COPD patients taking inhaled&#xD;
      glucocorticoids present with community-acquired pneumonia. This project will use both ex vivo&#xD;
      investigation of AM from human volunteers (never-smokers; smokers with normal spirometry; and&#xD;
      COPD subjects who are current or former smokers), and an established murine model of&#xD;
      pneumococcal pneumonia. Its immediate goals are to: (a) confirm that GCAE increases&#xD;
      pneumococcal pneumonia risk and severity, and in the process, validate a murine model for&#xD;
      testing strategies to reverse those defects; (b) define GCAE-induced AM defects functionally&#xD;
      and by whole-transcriptome analysis, identifying genes and miRNAs uniquely regulated by the&#xD;
      GCAE x pneumococcus interaction; (c) validate and optimize miRNA-over-expression to reverse&#xD;
      the adverse effects of GCAE on AM defensive functions. Successful completion of this project&#xD;
      could lead to more precisely personalized therapies and better outcomes in COPD, currently&#xD;
      the third leading cause of death in the USA&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 1, 2015</start_date>
  <completion_date type="Actual">December 30, 2021</completion_date>
  <primary_completion_date type="Actual">March 20, 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>This study will analyze both healthy subjects (never-smokers and current- or ex-smokers) in one arm, and also subjects with COPD (current- or ex-smokers).</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Bactericidal activity of human alveolar macrophage against S. pneumoniae in vitro</measure>
    <time_frame>24 hours</time_frame>
    <description>Alveolar macrophages from volunteers will be be assayed for their ability to kill pneumococci in vitro following treatment with glucocorticoids, apoptotic cells or both. Participation of the subjects ends after bronchoscopy, and no clinical outcomes will be measured.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Mechanisms of human alveolar macrophage killing of S. pneumoniae in vitro</measure>
    <time_frame>24 hours</time_frame>
    <description>These same macrophages will also be assayed for production of mRNA and regulatory microRNAs (by RNA sequencing and quantitative real-time PCR and for cytokine and chemokine production.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">60</enrollment>
  <condition>Pulmonary Disease, Chronic Obstructive</condition>
  <condition>Pneumonia, Bacterial</condition>
  <arm_group>
    <arm_group_label>Healthy Participants</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Procedure/Surgery: Bronchoscopy with bilateral bronchoalveolar lavages.&#xD;
Drugs: No test substances, only moderate conscious sedation using standard medications.&#xD;
Devices: No test devices.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>COPD participants</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Procedure/Surgery: Bronchoscopy with bilateral bronchoalveolar lavages.&#xD;
Drugs: No test substances, only moderate conscious sedation using standard medications.&#xD;
Devices: No test devices.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Bronchoscopy with bilateral bronchoalveolar lavages</intervention_name>
    <description>Bronchoscopy with bilateral bronchoalveolar lavages</description>
    <arm_group_label>COPD participants</arm_group_label>
    <arm_group_label>Healthy Participants</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Inclusion Criteria for healthy subjects without COPD:&#xD;
&#xD;
          -  Age 18-80 years, inclusive&#xD;
&#xD;
          -  Males or females&#xD;
&#xD;
          -  Never smoker (&lt; 100 cigarettes in lifetime)&#xD;
&#xD;
               -  OR&#xD;
&#xD;
          -  Current smoker (&gt;10 pack-years) with normal spirometry&#xD;
&#xD;
          -  Able to perform satisfactory spirometry&#xD;
&#xD;
          -  Abe to give informed consent&#xD;
&#xD;
          -  Able to complete questionnaires&#xD;
&#xD;
          -  Inclusion Criteria for COPD subjects:&#xD;
&#xD;
          -  Age 18-80 years, inclusive&#xD;
&#xD;
          -  Males or females&#xD;
&#xD;
          -  Current smoker&#xD;
&#xD;
               -  (&gt;10 pack-years) &amp; (≥1/2 pack/day)&#xD;
&#xD;
                    -  OR&#xD;
&#xD;
          -  Former smoker&#xD;
&#xD;
               -  (&gt;10 pack-years) &amp; (&gt;6 months of non-smoking)&#xD;
&#xD;
          -  Diagnosis of COPD by ATS/ERS1 criteria&#xD;
&#xD;
          -  Able to perform satisfactory spirometry&#xD;
&#xD;
          -  Able to give informed consent&#xD;
&#xD;
          -  Able to complete questionnaires&#xD;
&#xD;
          -  1 ATS/ERS, American Thoracic Society/European Respiratory Society.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Exclusion Criteria for healthy subjects without COPD:&#xD;
&#xD;
          -  Unstable cardiovascular disease, including uncontrolled hypertension, CHF, angina&#xD;
&#xD;
          -  Significant renal (creatinine &gt;2.5) or hepatic dysfunction (Childs B or C)&#xD;
&#xD;
          -  Mental incompetence/active psychiatric illness&#xD;
&#xD;
          -  Prednisone or other immunosuppressive medications&#xD;
&#xD;
          -  Participation in another interventional experimental protocol within 6 weeks&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Use of antibiotics for any reason within 42 days&#xD;
&#xD;
          -  Judged to be unsuitable for bronchoscopy by PI&#xD;
&#xD;
          -  Resting SaO2&lt;93%&#xD;
&#xD;
          -  FEV1 &lt; 70% predicted&#xD;
&#xD;
          -  Respiratory infections within 42 days regardless of antibiotic use&#xD;
&#xD;
          -  Diagnosed COPD or Asthma&#xD;
&#xD;
          -  Use of inhaled corticosteroids&#xD;
&#xD;
          -  Active pulmonary tuberculosis or other serious chronic respiratory infection&#xD;
&#xD;
          -  Diffuse panbronchiolitis or Cystic fibrosis&#xD;
&#xD;
          -  Clinically significant bronchiectasis&#xD;
&#xD;
          -  History of thoracic radiation therapy for any cause&#xD;
&#xD;
          -  Other inflammatory or fibrotic lung disease&#xD;
&#xD;
          -  Exclusion Criteria for COPD subjects:&#xD;
&#xD;
          -  Unstable cardiovascular disease, including uncontrolled hypertension, CHF, angina&#xD;
&#xD;
          -  Significant renal (creatinine &gt;2.5) or hepatic dysfunction (Childs B or C)&#xD;
&#xD;
          -  Mental incompetence/active psychiatric illness&#xD;
&#xD;
          -  Prednisone or other immunosuppressive medications&#xD;
&#xD;
          -  Participation in another interventional experimental protocol within 6 weeks&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Use of antibiotics for any reason within 42 days&#xD;
&#xD;
          -  Judged to be unsuitable for bronchoscopy by PI&#xD;
&#xD;
          -  Resting daytime SaO2&lt;90% while breathing room air&#xD;
&#xD;
          -  FEV1 &lt; 50% predicted&#xD;
&#xD;
          -  Respiratory infections within 42 days regardless of antibiotic use&#xD;
&#xD;
          -  Use of inhaled corticosteroids&#xD;
&#xD;
          -  Active pulmonary tuberculosis or other serious chronic respiratory infection&#xD;
&#xD;
          -  Diffuse panbronchiolitis or Cystic fibrosis&#xD;
&#xD;
          -  Clinically significant bronchiectasis&#xD;
&#xD;
          -  History of thoracic radiation therapy for any cause&#xD;
&#xD;
          -  Other inflammatory or fibrotic lung disease&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jeffrey L. Curtis, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Michigan</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>VA Ann Arbor Healthcare System</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>McCubbrey AL, Sonstein J, Ames TM, Freeman CM, Curtis JL. Glucocorticoids relieve collectin-driven suppression of apoptotic cell uptake in murine alveolar macrophages through downregulation of SIRPalpha. J Immunol. 2012 Jul 1;189(1):112-9. doi: 10.4049/jimmunol.1200984. Epub 2012 May 21.</citation>
    <PMID>22615206</PMID>
  </reference>
  <reference>
    <citation>Freeman CM, Martinez CH, Todt JC, Martinez FJ, Han MK, Thompson DL, McCloskey L, Curtis JL. Acute exacerbations of chronic obstructive pulmonary disease are associated with decreased CD4+ &amp; CD8+ T cells and increased growth &amp; differentiation factor-15 (GDF-15) in peripheral blood. Respir Res. 2015 Aug 5;16(1):94. doi: 10.1186/s12931-015-0251-1.</citation>
    <PMID>26243260</PMID>
  </reference>
  <reference>
    <citation>Adar SD, Huffnagle GB, Curtis JL. The respiratory microbiome: an underappreciated player in the human response to inhaled pollutants? Ann Epidemiol. 2016 May;26(5):355-9. doi: 10.1016/j.annepidem.2016.03.010. Epub 2016 Apr 7.</citation>
    <PMID>27161078</PMID>
  </reference>
  <reference>
    <citation>Huang YJ, Erb-Downward JR, Dickson RP, Curtis JL, Huffnagle GB, Han MK. Understanding the role of the microbiome in chronic obstructive pulmonary disease: principles, challenges, and future directions. Transl Res. 2017 Jan;179:71-83. doi: 10.1016/j.trsl.2016.06.007. Epub 2016 Jun 23.</citation>
    <PMID>27392936</PMID>
  </reference>
  <reference>
    <citation>Freeman CM, Curtis JL. Lung Dendritic Cells: Shaping Immune Responses throughout Chronic Obstructive Pulmonary Disease Progression. Am J Respir Cell Mol Biol. 2017 Feb;56(2):152-159. doi: 10.1165/rcmb.2016-0272TR.</citation>
    <PMID>27767327</PMID>
  </reference>
  <reference>
    <citation>Verhamme FM, Freeman CM, Brusselle GG, Bracke KR, Curtis JL. GDF-15 in Pulmonary and Critical Care Medicine. Am J Respir Cell Mol Biol. 2019 Jun;60(6):621-628. doi: 10.1165/rcmb.2018-0379TR.</citation>
    <PMID>30633545</PMID>
  </reference>
  <reference>
    <citation>Freeman CM, Curtis JL. It's Complicated: Lung Dendritic Cells in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2020 Aug 15;202(4):479-481. doi: 10.1164/rccm.202004-0899ED. No abstract available.</citation>
    <PMID>32286855</PMID>
  </reference>
  <reference>
    <citation>Polverino F, Curtis JL. The ABCs of Granulomatous Lung Diseases: Age-associated B Cells. Am J Respir Crit Care Med. 2020 Oct 1;202(7):922-924. doi: 10.1164/rccm.202006-2261ED. No abstract available.</citation>
    <PMID>32603192</PMID>
  </reference>
  <reference>
    <citation>He Y, Wang H, Zheng J, Beiting DP, Masci AM, Yu H, Liu K, Wu J, Curtis JL, Smith B, Alekseyenko AV, Obeid JS. OHMI: the ontology of host-microbiome interactions. J Biomed Semantics. 2019 Dec 30;10(1):25. doi: 10.1186/s13326-019-0217-1.</citation>
    <PMID>31888755</PMID>
  </reference>
  <reference>
    <citation>Tighe RM, Redente EF, Yu YR, Herold S, Sperling AI, Curtis JL, Duggan R, Swaminathan S, Nakano H, Zacharias WJ, Janssen WJ, Freeman CM, Brinkman RR, Singer BD, Jakubzick CV, Misharin AV. Improving the Quality and Reproducibility of Flow Cytometry in the Lung. An Official American Thoracic Society Workshop Report. Am J Respir Cell Mol Biol. 2019 Aug;61(2):150-161. doi: 10.1165/rcmb.2019-0191ST.</citation>
    <PMID>31368812</PMID>
  </reference>
  <reference>
    <citation>Curtis JL. B Cells Caught in the Act: Class Switching to IgA in Lung Lymphoid Follicles in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2019 Mar 1;199(5):548-550. doi: 10.1164/rccm.201810-1907ED. No abstract available.</citation>
    <PMID>30352169</PMID>
  </reference>
  <results_reference>
    <citation>Stolberg VR, McCubbrey AL, Freeman CM, Brown JP, Crudgington SW, Taitano SH, Saxton BL, Mancuso P, Curtis JL. Glucocorticoid-Augmented Efferocytosis Inhibits Pulmonary Pneumococcal Clearance in Mice by Reducing Alveolar Macrophage Bactericidal Function. J Immunol. 2015 Jul 1;195(1):174-84. doi: 10.4049/jimmunol.1402217. Epub 2015 May 18.</citation>
    <PMID>25987742</PMID>
  </results_reference>
  <results_reference>
    <citation>McCubbrey AL, Nelson JD, Stolberg VR, Blakely PK, McCloskey L, Janssen WJ, Freeman CM, Curtis JL. MicroRNA-34a Negatively Regulates Efferocytosis by Tissue Macrophages in Part via SIRT1. J Immunol. 2016 Feb 1;196(3):1366-75. doi: 10.4049/jimmunol.1401838. Epub 2015 Dec 30.</citation>
    <PMID>26718338</PMID>
  </results_reference>
  <results_reference>
    <citation>Dickson RP, Erb-Downward JR, Freeman CM, McCloskey L, Beck JM, Huffnagle GB, Curtis JL. Spatial Variation in the Healthy Human Lung Microbiome and the Adapted Island Model of Lung Biogeography. Ann Am Thorac Soc. 2015 Jun;12(6):821-30. doi: 10.1513/AnnalsATS.201501-029OC.</citation>
    <PMID>25803243</PMID>
  </results_reference>
  <results_reference>
    <citation>Dickson RP, Erb-Downward JR, Freeman CM, McCloskey L, Falkowski NR, Huffnagle GB, Curtis JL. Bacterial Topography of the Healthy Human Lower Respiratory Tract. mBio. 2017 Feb 14;8(1):e02287-16. doi: 10.1128/mBio.02287-16.</citation>
    <PMID>28196961</PMID>
  </results_reference>
  <results_reference>
    <citation>Dickson RP, Erb-Downward JR, Prescott HC, Martinez FJ, Curtis JL, Lama VN, Huffnagle GB. Intraalveolar Catecholamines and the Human Lung Microbiome. Am J Respir Crit Care Med. 2015 Jul 15;192(2):257-9. doi: 10.1164/rccm.201502-0326LE. No abstract available.</citation>
    <PMID>26177175</PMID>
  </results_reference>
  <results_reference>
    <citation>Mancuso P, Curtis JL, Freeman CM, Peters-Golden M, Weinberg JB, Myers MG Jr. Ablation of the leptin receptor in myeloid cells impairs pulmonary clearance of Streptococcus pneumoniae and alveolar macrophage bactericidal function. Am J Physiol Lung Cell Mol Physiol. 2018 Jul 1;315(1):L78-L86. doi: 10.1152/ajplung.00447.2017. Epub 2018 Mar 22.</citation>
    <PMID>29565180</PMID>
  </results_reference>
  <results_reference>
    <citation>Finch DK, Stolberg VR, Ferguson J, Alikaj H, Kady MR, Richmond BW, Polosukhin VV, Blackwell TS, McCloskey L, Curtis JL, Freeman CM. Lung Dendritic Cells Drive Natural Killer Cytotoxicity in Chronic Obstructive Pulmonary Disease via IL-15Ralpha. Am J Respir Crit Care Med. 2018 Nov 1;198(9):1140-1150. doi: 10.1164/rccm.201712-2513OC.</citation>
    <PMID>29676596</PMID>
  </results_reference>
  <results_reference>
    <citation>Erb-Downward JR, Falkowski NR, D'Souza JC, McCloskey LM, McDonald RA, Brown CA, Shedden K, Dickson RP, Freeman CM, Stringer KA, Foxman B, Huffnagle GB, Curtis JL, Adar SD. Critical Relevance of Stochastic Effects on Low-Bacterial-Biomass 16S rRNA Gene Analysis. mBio. 2020 Jun 9;11(3):e00258-20. doi: 10.1128/mBio.00258-20.</citation>
    <PMID>32518181</PMID>
  </results_reference>
  <results_reference>
    <citation>Yue M, Kim JH, Evans CR, Kachman M, Erb-Downward JR, D'Souza J, Foxman B, Adar SD, Curtis JL, Stringer KA. Measurement of Short-Chain Fatty Acids in Respiratory Samples: Keep Your Assay above the Water Line. Am J Respir Crit Care Med. 2020 Aug 15;202(4):610-612. doi: 10.1164/rccm.201909-1840LE. No abstract available.</citation>
    <PMID>32343599</PMID>
  </results_reference>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>January 23, 2017</study_first_submitted>
  <study_first_submitted_qc>January 24, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 27, 2017</study_first_posted>
  <last_update_submitted>April 26, 2022</last_update_submitted>
  <last_update_submitted_qc>April 26, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 3, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>VA Ann Arbor Healthcare System</investigator_affiliation>
    <investigator_full_name>Jeffrey Curtis</investigator_full_name>
    <investigator_title>Staff Physician</investigator_title>
  </responsible_party>
  <keyword>Apoptosis</keyword>
  <keyword>Bronchoscopy</keyword>
  <keyword>Human</keyword>
  <keyword>Mice, inbred strains</keyword>
  <keyword>Macrophages, Alveolar</keyword>
  <keyword>MicroRNAs</keyword>
  <keyword>Streptococcus pneumoniae</keyword>
  <keyword>Fluticasone</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pneumonia</mesh_term>
    <mesh_term>Pneumonia, Bacterial</mesh_term>
    <mesh_term>Pulmonary Disease, Chronic Obstructive</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dimercaprol</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03034642
org study id: VAAAHS Curtis 0038
secondary id: I01CX000911
nct id: NCT03034642
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The long-term goals of this study are (a) to understand the biological underpinnings for the
      increased incidence of community-acquired pneumonia in patients with chronic obstructive
      pulmonary disease (COPD) who are treated with inhaled corticosteroids; and (b) to develop
      novel therapies to treated this problem using over-expression of micro-RNAs (miRNAs).
Treating chronic obstructive pulmonary disease (COPD) patients with inhaled
      glucocorticosteroids has been convincingly shown to increase their risk of pneumonia, but the
      responsible mechanisms are undefined. Work from this laboratory suggests a possible
      mechanism, related to the increased numbers of cells dying by apoptosis in the lungs in COPD,
      especially in emphysema. Uptake of apoptotic cells ("efferocytosis") suppresses the ability
      of alveolar macrophages (AM) to fight infections. By markedly increasing AM efferocytosis,
      glucocorticoids plus apoptotic cells cause greater immune defects than either stimulus alone.
      These defects include reductions in killing of Streptococcus pneumoniae by human AM and
      murine AM in vitro, and in clearance of viable pneumococci from lungs of mice. This effect is
      called glucocorticoid augmented efferocytosis (GCAE). MicroRNAs (miRNAs) are 19-25
      nucleotide-long non-coding RNAs that coordinately target large numbers of genes and reduce
      their protein products. Preliminary data imply that defective AM function is caused by
      down-regulation of specific miRNAs by GCAE (but not by apoptotic cells alone or
      glucocorticosteroids alone). The long-term goal of this project is to develop novel
      inhalational treatments based on transient over-expression of these specifically decreased
      miRNAs, to reverse defective AM immune function when COPD patients taking inhaled
      glucocorticoids present with community-acquired pneumonia. This project will use both ex vivo
      investigation of AM from human volunteers (never-smokers; smokers with normal spirometry; and
      COPD subjects who are current or former smokers), and an established murine model of
      pneumococcal pneumonia. Its immediate goals are to: (a) confirm that GCAE increases
      pneumococcal pneumonia risk and severity, and in the process, validate a murine model for
      testing strategies to reverse those defects; (b) define GCAE-induced AM defects functionally
      and by whole-transcriptome analysis, identifying genes and miRNAs uniquely regulated by the
      GCAE x pneumococcus interaction; (c) validate and optimize miRNA-over-expression to reverse
      the adverse effects of GCAE on AM defensive functions. Successful completion of this project
      could lead to more precisely personalized therapies and better outcomes in COPD, currently
      the third leading cause of death in the USA
allocation: Non-Randomized
intervention model: Parallel Assignment
intervention model description: This study will analyze both healthy subjects (never-smokers and current- or ex-smokers) in one arm, and also subjects with COPD (current- or ex-smokers).
primary purpose: Basic Science
masking: None (Open Label)
measure: Bactericidal activity of human alveolar macrophage against S. pneumoniae in vitro
time frame: 24 hours
description: Alveolar macrophages from volunteers will be be assayed for their ability to kill pneumococci in vitro following treatment with glucocorticoids, apoptotic cells or both. Participation of the subjects ends after bronchoscopy, and no clinical outcomes will be measured.
measure: Mechanisms of human alveolar macrophage killing of S. pneumoniae in vitro
time frame: 24 hours
description: These same macrophages will also be assayed for production of mRNA and regulatory microRNAs (by RNA sequencing and quantitative real-time PCR and for cytokine and chemokine production.
arm group label: Healthy Participants
arm group type: Experimental
description: Procedure/Surgery: Bronchoscopy with bilateral bronchoalveolar lavages.
Drugs: No test substances, only moderate conscious sedation using standard medications.
Devices: No test devices.
arm group label: COPD participants
arm group type: Experimental
description: Procedure/Surgery: Bronchoscopy with bilateral bronchoalveolar lavages.
Drugs: No test substances, only moderate conscious sedation using standard medications.
Devices: No test devices.
intervention type: Procedure
intervention name: Bronchoscopy with bilateral bronchoalveolar lavages
description: Bronchoscopy with bilateral bronchoalveolar lavages
arm group label: COPD participants
arm group label: Healthy Participants
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Jeffrey L. Curtis, M.D.
role: Principal Investigator
affiliation: University of Michigan
facility: 
country: United States
citation: McCubbrey AL, Sonstein J, Ames TM, Freeman CM, Curtis JL. Glucocorticoids relieve collectin-driven suppression of apoptotic cell uptake in murine alveolar macrophages through downregulation of SIRPalpha. J Immunol. 2012 Jul 1;189(1):112-9. doi: 10.4049/jimmunol.1200984. Epub 2012 May 21.
PMID: 22615206
citation: Freeman CM, Martinez CH, Todt JC, Martinez FJ, Han MK, Thompson DL, McCloskey L, Curtis JL. Acute exacerbations of chronic obstructive pulmonary disease are associated with decreased CD4+ & CD8+ T cells and increased growth & differentiation factor-15 (GDF-15) in peripheral blood. Respir Res. 2015 Aug 5;16(1):94. doi: 10.1186/s12931-015-0251-1.
PMID: 26243260
citation: Adar SD, Huffnagle GB, Curtis JL. The respiratory microbiome: an underappreciated player in the human response to inhaled pollutants? Ann Epidemiol. 2016 May;26(5):355-9. doi: 10.1016/j.annepidem.2016.03.010. Epub 2016 Apr 7.
PMID: 27161078
citation: Huang YJ, Erb-Downward JR, Dickson RP, Curtis JL, Huffnagle GB, Han MK. Understanding the role of the microbiome in chronic obstructive pulmonary disease: principles, challenges, and future directions. Transl Res. 2017 Jan;179:71-83. doi: 10.1016/j.trsl.2016.06.007. Epub 2016 Jun 23.
PMID: 27392936
citation: Freeman CM, Curtis JL. Lung Dendritic Cells: Shaping Immune Responses throughout Chronic Obstructive Pulmonary Disease Progression. Am J Respir Cell Mol Biol. 2017 Feb;56(2):152-159. doi: 10.1165/rcmb.2016-0272TR.
PMID: 27767327
citation: Verhamme FM, Freeman CM, Brusselle GG, Bracke KR, Curtis JL. GDF-15 in Pulmonary and Critical Care Medicine. Am J Respir Cell Mol Biol. 2019 Jun;60(6):621-628. doi: 10.1165/rcmb.2018-0379TR.
PMID: 30633545
citation: Freeman CM, Curtis JL. It's Complicated: Lung Dendritic Cells in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2020 Aug 15;202(4):479-481. doi: 10.1164/rccm.202004-0899ED. No abstract available.
PMID: 32286855
citation: Polverino F, Curtis JL. The ABCs of Granulomatous Lung Diseases: Age-associated B Cells. Am J Respir Crit Care Med. 2020 Oct 1;202(7):922-924. doi: 10.1164/rccm.202006-2261ED. No abstract available.
PMID: 32603192
citation: He Y, Wang H, Zheng J, Beiting DP, Masci AM, Yu H, Liu K, Wu J, Curtis JL, Smith B, Alekseyenko AV, Obeid JS. OHMI: the ontology of host-microbiome interactions. J Biomed Semantics. 2019 Dec 30;10(1):25. doi: 10.1186/s13326-019-0217-1.
PMID: 31888755
citation: Tighe RM, Redente EF, Yu YR, Herold S, Sperling AI, Curtis JL, Duggan R, Swaminathan S, Nakano H, Zacharias WJ, Janssen WJ, Freeman CM, Brinkman RR, Singer BD, Jakubzick CV, Misharin AV. Improving the Quality and Reproducibility of Flow Cytometry in the Lung. An Official American Thoracic Society Workshop Report. Am J Respir Cell Mol Biol. 2019 Aug;61(2):150-161. doi: 10.1165/rcmb.2019-0191ST.
PMID: 31368812
citation: Curtis JL. B Cells Caught in the Act: Class Switching to IgA in Lung Lymphoid Follicles in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2019 Mar 1;199(5):548-550. doi: 10.1164/rccm.201810-1907ED. No abstract available.
PMID: 30352169
citation: Stolberg VR, McCubbrey AL, Freeman CM, Brown JP, Crudgington SW, Taitano SH, Saxton BL, Mancuso P, Curtis JL. Glucocorticoid-Augmented Efferocytosis Inhibits Pulmonary Pneumococcal Clearance in Mice by Reducing Alveolar Macrophage Bactericidal Function. J Immunol. 2015 Jul 1;195(1):174-84. doi: 10.4049/jimmunol.1402217. Epub 2015 May 18.
PMID: 25987742
citation: McCubbrey AL, Nelson JD, Stolberg VR, Blakely PK, McCloskey L, Janssen WJ, Freeman CM, Curtis JL. MicroRNA-34a Negatively Regulates Efferocytosis by Tissue Macrophages in Part via SIRT1. J Immunol. 2016 Feb 1;196(3):1366-75. doi: 10.4049/jimmunol.1401838. Epub 2015 Dec 30.
PMID: 26718338
citation: Dickson RP, Erb-Downward JR, Freeman CM, McCloskey L, Beck JM, Huffnagle GB, Curtis JL. Spatial Variation in the Healthy Human Lung Microbiome and the Adapted Island Model of Lung Biogeography. Ann Am Thorac Soc. 2015 Jun;12(6):821-30. doi: 10.1513/AnnalsATS.201501-029OC.
PMID: 25803243
citation: Dickson RP, Erb-Downward JR, Freeman CM, McCloskey L, Falkowski NR, Huffnagle GB, Curtis JL. Bacterial Topography of the Healthy Human Lower Respiratory Tract. mBio. 2017 Feb 14;8(1):e02287-16. doi: 10.1128/mBio.02287-16.
PMID: 28196961
citation: Dickson RP, Erb-Downward JR, Prescott HC, Martinez FJ, Curtis JL, Lama VN, Huffnagle GB. Intraalveolar Catecholamines and the Human Lung Microbiome. Am J Respir Crit Care Med. 2015 Jul 15;192(2):257-9. doi: 10.1164/rccm.201502-0326LE. No abstract available.
PMID: 26177175
citation: Mancuso P, Curtis JL, Freeman CM, Peters-Golden M, Weinberg JB, Myers MG Jr. Ablation of the leptin receptor in myeloid cells impairs pulmonary clearance of Streptococcus pneumoniae and alveolar macrophage bactericidal function. Am J Physiol Lung Cell Mol Physiol. 2018 Jul 1;315(1):L78-L86. doi: 10.1152/ajplung.00447.2017. Epub 2018 Mar 22.
PMID: 29565180
citation: Finch DK, Stolberg VR, Ferguson J, Alikaj H, Kady MR, Richmond BW, Polosukhin VV, Blackwell TS, McCloskey L, Curtis JL, Freeman CM. Lung Dendritic Cells Drive Natural Killer Cytotoxicity in Chronic Obstructive Pulmonary Disease via IL-15Ralpha. Am J Respir Crit Care Med. 2018 Nov 1;198(9):1140-1150. doi: 10.1164/rccm.201712-2513OC.
PMID: 29676596
citation: Erb-Downward JR, Falkowski NR, D'Souza JC, McCloskey LM, McDonald RA, Brown CA, Shedden K, Dickson RP, Freeman CM, Stringer KA, Foxman B, Huffnagle GB, Curtis JL, Adar SD. Critical Relevance of Stochastic Effects on Low-Bacterial-Biomass 16S rRNA Gene Analysis. mBio. 2020 Jun 9;11(3):e00258-20. doi: 10.1128/mBio.00258-20.
PMID: 32518181
citation: Yue M, Kim JH, Evans CR, Kachman M, Erb-Downward JR, D'Souza J, Foxman B, Adar SD, Curtis JL, Stringer KA. Measurement of Short-Chain Fatty Acids in Respiratory Samples: Keep Your Assay above the Water Line. Am J Respir Crit Care Med. 2020 Aug 15;202(4):610-612. doi: 10.1164/rccm.201909-1840LE. No abstract available.
PMID: 32343599
responsible party type: Principal Investigator
investigator affiliation: VA Ann Arbor Healthcare System
investigator full name: Jeffrey Curtis
investigator title: Staff Physician
mesh term: Pneumonia
mesh term: Pneumonia, Bacterial
mesh term: Pulmonary Disease, Chronic Obstructive
mesh term: Dimercaprol
sharing ipd: No