Modulation of Steroid Immunosuppression by Alveolar Efferocytosis

NCT ID: NCT03034642

Last Updated: 2022-05-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-10-01
• Study Completion Date: 2021-12-30

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).

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

Conditions

Pulmonary Disease, Chronic Obstructive; Pneumonia, Bacterial

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Healthy Participants

Procedure/Surgery: Bronchoscopy with bilateral bronchoalveolar lavages.

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

Devices: No test devices.

Group Type: EXPERIMENTAL

Bronchoscopy with bilateral bronchoalveolar lavages

Intervention Type: PROCEDURE

Bronchoscopy with bilateral bronchoalveolar lavages

COPD participants

Procedure/Surgery: Bronchoscopy with bilateral bronchoalveolar lavages.

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

Devices: No test devices.

Group Type: EXPERIMENTAL

Bronchoscopy with bilateral bronchoalveolar lavages

Intervention Type: PROCEDURE

Bronchoscopy with bilateral bronchoalveolar lavages

Interventions

Bronchoscopy with bilateral bronchoalveolar lavages

Bronchoscopy with bilateral bronchoalveolar lavages

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

• 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
• 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

• 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
• 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Michigan

OTHER

Sponsor Role: collaborator

VA Ann Arbor Healthcare System

FED

Sponsor Role: lead

Responsible Party

Jeffrey Curtis

Staff Physician

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jeffrey L. Curtis, M.D.

Role: PRINCIPAL_INVESTIGATOR

University of Michigan

Locations

VA Ann Arbor Healthcare System

Ann Arbor, Michigan, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 22615206 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26243260 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 27161078 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 27392936 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 27767327 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 30633545 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 32286855 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 32603192 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 31888755 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 31368812 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 30352169 (View on PubMed)

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.

Reference Type: RESULT

PMID: 25987742 (View on PubMed)

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.

Reference Type: RESULT

PMID: 26718338 (View on PubMed)

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.

Reference Type: RESULT

PMID: 25803243 (View on PubMed)

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.

Reference Type: RESULT

PMID: 28196961 (View on PubMed)

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.

Reference Type: RESULT

PMID: 26177175 (View on PubMed)

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.

Reference Type: RESULT

PMID: 29565180 (View on PubMed)

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.

Reference Type: RESULT

PMID: 29676596 (View on PubMed)

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.

Reference Type: RESULT

PMID: 32518181 (View on PubMed)

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.

Reference Type: RESULT

PMID: 32343599 (View on PubMed)

Other Identifiers

I01CX000911

Identifier Type: NIH

Identifier Source: secondary_id

View Link

VAAAHS Curtis 0038

Identifier Type: -

Identifier Source: org_study_id