Modulation of Steroid Immunosuppression by Alveolar Efferocytosis

NCT03034642 | Completed

• 2 other identifiers: VAAAHS Curtis 0038I01CX000911
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

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).

Conditions

Pulmonary Disease, Chronic Obstructive; Pneumonia, Bacterial

Keywords

Apoptosis; Bronchoscopy; Human; Mice, inbred strains; Macrophages, Alveolar; MicroRNAs; Streptococcus pneumoniae; Fluticasone

Outcome Measures

Primary Outcomes (1)

• Bactericidal activity of human alveolar macrophage against S. pneumoniae in vitro

  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 Outcomes (1)

• Mechanisms of human alveolar macrophage killing of S. pneumoniae in vitro

  24 hours

Study Arms (2)

Healthy Participants

EXPERIMENTAL

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

COPD participants

EXPERIMENTAL

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

Interventions

Bronchoscopy with bilateral bronchoalveolar lavages PROCEDURE

Bronchoscopy with bilateral bronchoalveolar lavages

COPD participants; Healthy Participants

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18-80 years, inclusive
• Males or females
• Never smoker (\< 100 cigarettes in lifetime)
• Current smoker (\>10 pack-years) with normal spirometry
• Able to perform satisfactory spirometry
• Abe to give informed consent
• Able to complete questionnaires
• Age 18-80 years, inclusive
• Males or females
• Current smoker
• (\>10 pack-years) \& (≥1/2 pack/day)
• Former smoker
• (\>10 pack-years) \& (\>6 months of non-smoking)
• Diagnosis of COPD by ATS/ERS1 criteria
• Able to perform satisfactory spirometry

You may not qualify if:

• 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

Sponsors & Collaborators

• VA Ann Arbor Healthcare System: lead
• University of Michigan: collaborator

Study Sites (1)

VA Ann Arbor Healthcare System

Ann Arbor, Michigan, 48105, United States

Location

Related Publications (20)

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive; Pneumonia, Bacterial

Interventions

Bronchoscopy

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Pneumonia; Respiratory Tract Infections

Intervention Hierarchy (Ancestors)

Diagnostic Techniques, Respiratory System; Diagnostic Techniques and Procedures; Diagnosis; Endoscopy; Diagnostic Techniques, Surgical; Minimally Invasive Surgical Procedures; Surgical Procedures, Operative; Pulmonary Surgical Procedures; Thoracic Surgical Procedures

Study Officials

• Jeffrey L. Curtis, M.D.

  University of Michigan

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Staff Physician

Model Details: 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).

Study Record Dates

• First Submitted: January 23, 2017
• First Posted: January 27, 2017
• Study Start: October 1, 2015
• Primary Completion: March 20, 2020
• Study Completion: December 30, 2021
• Last Updated: May 3, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)