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Modulation of Steroid Immunosuppression by Alveolar Efferocytosis

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ClinicalTrials.gov Identifier: NCT03034642
Recruitment Status : Recruiting
First Posted : January 27, 2017
Last Update Posted : June 14, 2019
Sponsor:
Collaborator:
VA Ann Arbor Healthcare System
Information provided by (Responsible Party):
Jeffrey L. Curtis, University of Michigan

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Pulmonary Disease, Chronic Obstructive Pneumonia, Bacterial Procedure: Bronchoscopy with bilateral bronchoalveolar lavages Not Applicable

Detailed Description:
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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
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).
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Modulation of Steroid Immunosuppression by Alveolar Efferocytosis
Study Start Date : October 2015
Estimated Primary Completion Date : September 30, 2020
Estimated Study Completion Date : December 30, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Pneumonia

Arm Intervention/treatment
Experimental: Healthy Participants

Procedure/Surgery: Bronchoscopy with bilateral bronchoalveolar lavages.

Drugs: No test substances, only moderate conscious sedation using standard medications.

Devices: No test devices.

Procedure: Bronchoscopy with bilateral bronchoalveolar lavages
Bronchoscopy with bilateral bronchoalveolar lavages

Experimental: COPD participants

Procedure/Surgery: Bronchoscopy with bilateral bronchoalveolar lavages.

Drugs: No test substances, only moderate conscious sedation using standard medications.

Devices: No test devices.

Procedure: Bronchoscopy with bilateral bronchoalveolar lavages
Bronchoscopy with bilateral bronchoalveolar lavages




Primary Outcome Measures :
  1. Bactericidal activity of human alveolar macrophage against S. pneumoniae in vitro [ Time Frame: 24 hours ]
    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.


Secondary Outcome Measures :
  1. Mechanisms of human alveolar macrophage killing of S. pneumoniae in vitro [ Time Frame: 24 hours ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Inclusion Criteria for healthy subjects without COPD:
  • Age 18-80 years, inclusive
  • Males or females
  • Never smoker (< 100 cigarettes in lifetime)

    • OR
  • Current smoker (>10 pack-years) with normal spirometry
  • Able to perform satisfactory spirometry
  • Abe to give informed consent
  • Able to complete questionnaires
  • Inclusion Criteria for COPD subjects:
  • Age 18-80 years, inclusive
  • Males or females
  • Current smoker

    • (>10 pack-years) & (≥1/2 pack/day)

      • OR
  • Former smoker

    • (>10 pack-years) & (>6 months of non-smoking)
  • Diagnosis of COPD by ATS/ERS1 criteria
  • Able to perform satisfactory spirometry
  • Able to give informed consent
  • Able to complete questionnaires
  • 1 ATS/ERS, American Thoracic Society/European Respiratory Society.

Exclusion Criteria:

  • Exclusion Criteria for healthy subjects without COPD:
  • Unstable cardiovascular disease, including uncontrolled hypertension, CHF, angina
  • Significant renal (creatinine >2.5) or hepatic dysfunction (Childs B or C)
  • Mental incompetence/active psychiatric illness
  • Prednisone or other immunosuppressive medications
  • Participation in another interventional experimental protocol within 6 weeks
  • Pregnancy
  • Use of antibiotics for any reason within 42 days
  • Judged to be unsuitable for bronchoscopy by PI
  • Resting SaO2<93%
  • FEV1 < 70% predicted
  • Respiratory infections within 42 days regardless of antibiotic use
  • Diagnosed COPD or Asthma
  • Use of inhaled corticosteroids
  • Active pulmonary tuberculosis or other serious chronic respiratory infection
  • Diffuse panbronchiolitis or Cystic fibrosis
  • Clinically significant bronchiectasis
  • History of thoracic radiation therapy for any cause
  • Other inflammatory or fibrotic lung disease
  • Exclusion Criteria for COPD subjects:
  • Unstable cardiovascular disease, including uncontrolled hypertension, CHF, angina
  • Significant renal (creatinine >2.5) or hepatic dysfunction (Childs B or C)
  • Mental incompetence/active psychiatric illness
  • Prednisone or other immunosuppressive medications
  • Participation in another interventional experimental protocol within 6 weeks
  • Pregnancy
  • Use of antibiotics for any reason within 42 days
  • Judged to be unsuitable for bronchoscopy by PI
  • Resting daytime SaO2<90% while breathing room air
  • FEV1 < 50% predicted
  • Respiratory infections within 42 days regardless of antibiotic use
  • Use of inhaled corticosteroids
  • Active pulmonary tuberculosis or other serious chronic respiratory infection
  • Diffuse panbronchiolitis or Cystic fibrosis
  • Clinically significant bronchiectasis
  • History of thoracic radiation therapy for any cause
  • Other inflammatory or fibrotic lung disease

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03034642


Contacts
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Contact: Lisa McCloskey, B.S., R.R.T. 734-845-3533 lmcclosk@umich.edu
Contact: Jeffrey L. Curtis, M.D. 734-845-3457 jlcurtis@umich.edu

Locations
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United States, Michigan
VA Ann Arbor Healthcare System Recruiting
Ann Arbor, Michigan, United States, 48105
Contact: Lisa McCloskey, RRT    734-835-3533    lmcclosk@umich.edu   
Contact: Jeffrey L. Curtis, MD    734-845-5679    jlcurtis@umich.edu   
Principal Investigator: Jeffrey L. Curtis, M.D.         
Sponsors and Collaborators
University of Michigan
VA Ann Arbor Healthcare System
Investigators
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Principal Investigator: Jeffrey L. Curtis, M.D. University of Michigan

Publications of Results:

Other Publications:

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Responsible Party: Jeffrey L. Curtis, Professor of Internal Medicine & Staff Physician, University of Michigan
ClinicalTrials.gov Identifier: NCT03034642     History of Changes
Other Study ID Numbers: VAAAHS Curtis 0038
I01CX000911 ( U.S. NIH Grant/Contract )
First Posted: January 27, 2017    Key Record Dates
Last Update Posted: June 14, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: de-identified participant data will be made available at study completion

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Jeffrey L. Curtis, University of Michigan:
Apoptosis
Bronchoscopy
Human
Mice, inbred strains
Macrophages, Alveolar
MicroRNAs
Streptococcus pneumoniae
Fluticasone

Additional relevant MeSH terms:
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Pneumonia, Bacterial
Lung Diseases
Pneumonia
Pulmonary Disease, Chronic Obstructive
Chronic Disease
Respiratory Tract Diseases
Respiratory Tract Infections
Disease Attributes
Pathologic Processes
Lung Diseases, Obstructive
Bacterial Infections