Modulation of Steroid Immunosuppression by Alveolar Efferocytosis

April 26, 2022 updated by: Jeffrey Curtis, VA Ann Arbor Healthcare System
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).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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

Study Type

Interventional

Enrollment (Actual)

60

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Michigan
      • Ann Arbor, Michigan, United States, 48105
        • VA Ann Arbor Healthcare System

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 78 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
24 hours

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
24 hours

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

VA Ann Arbor Healthcare System

Collaborators

University of Michigan

Investigators

  • Principal Investigator: Jeffrey L. Curtis, M.D., University of Michigan

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 1, 2015

Primary Completion (Actual)

March 20, 2020

Study Completion (Actual)

December 30, 2021

Study Registration Dates

First Submitted

January 23, 2017

First Submitted That Met QC Criteria

January 24, 2017

First Posted (Estimate)

January 27, 2017

Study Record Updates

Last Update Posted (Actual)

May 3, 2022

Last Update Submitted That Met QC Criteria

April 26, 2022

Last Verified

April 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • VAAAHS Curtis 0038
  • I01CX000911 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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