Lung Disease and Its Affect on the Work of White Blood Cells in the Lungs

The Role of Conformational Diseases on Macrophage Function

The purpose of this study is to look at how Alpha-1-antitrypsin (AAT) deficiency and Cystic Fibrosis (CF) affect white blood cells in the lungs, called macrophages, and their ability to work.

Study Overview

• Status: Recruiting
• Conditions: Alpha-1 Antitrypsin Deficiency; Cystic Fibrosis (CF); AATD; AAT Deficiency
• Intervention / Treatment: Procedure: History and physical exam.; Procedure: Blood draw.; Procedure: Pulmonary function testing.; Drug: Albuterol inhaler.

Detailed Description

AAT deficiency is a genetic disorder that affects around 100,000 people in the USA, including 1-3% of all people diagnosed with chronic obstructive pulmonary disease (COPD). In AAT deficient people diagnosed with COPD, it was originally believed the cause of the disease was due to a lack of supply of alpha-1 antitrypsin. However, early information gathered in our laboratory suggests another cause of the development of COPD and the progressing of the disease may be due to a malfunction in macrophages.

CF is also a genetic disorder which affects 1/300 births among the Caucasian population. One of the main symptoms of CF is inflammation of the lung tissue. Lung macrophages play a major role in lung inflammation as well as in helping to resolve the inflammation.

Inflammation is an important defense of the body. It is the body's response to infection causing germs and things that may cause irritation, as well as, a way for the body to repair damaged tissue.

We suggest that the effects of AAT deficiency and CF decreases the inflammation response in the lungs and also restricts the ability of macrophages to correct that inflammation once it occurs.

• Study Type: Observational
• Enrollment (Estimated): 220

Contacts and Locations

• Study Contact: Name: Jesse R West, RN, CCRC; Phone Number: 352-273-8666; Email: jesse.west@medicine.ufl.edu
• Study Contact Backup: Name: Michelle Owens, RN, BSN; Phone Number: 352-273-8990; Email: christina.eagan@medicine.ufl.edu

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32610
      • Recruiting
      • Shands at the University of Florida
      • Principal Investigator: Mark Brantly, MD
      • Contact: Jesse West, RN; Phone Number: 352-273-8666; Email: jesse.west@medicine.ufl.edu
      • Contact: Michelle Owens, RN,BSN; Phone Number: 352-273-6339; Email: sandra.owens@medicine.ufl.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Alpha-1 Antitrypsin (AAT) Deficient subjects, Cystic Fibrosis(CF) subjects with mutation Delta F508, and subjects without either diagnosis.

Description

Inclusion Criteria:

• Signed informed consent
• Male or female 18 years of age or older
• Negative pregnancy test for women of childbearing potential
• Hemoglobin >12.5 g/dl measured on the day of participation
• Negative urine nicotine test

Exclusion Criteria:

• Pregnancy or breastfeeding
• Weight < 50 kg
• History of anemia requiring blood transfusions, erythropoietin supplementation, or iron supplementation within the past 36 months
• Known hemoglobin <12.5 g/dl within the past 90 days
• Systolic blood pressure > 180 mmHg and/or diastolic blood pressure >100 mmHg
• Poor venous access
• Large volume blood donation (>200 ml or 7 ounces) within the previous 56 days (e.g. blood donation for the purposes of blood banking)
• Clinically significant cardiac, hemostatic or neurological impairment or any other significant medical condition that, in the opinion of the investigator would affect subject safety (e.g., recent myocardial infarction, history of prolonged bleeding time, cerebral vascular accident, advanced cancer or uncontrolled medical condition)
• Psychiatric or cognitive disturbance or illness that would affect subject safety
• Current smoker

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
AAT Deficiency; Those diagnosed with Alpha-1 Antitrypsin (AAT) Deficiency. At every study visit, a history and physical exam (H&P), blood draw, and pulmonary function testing (PFTs) with the use of an albuterol inhaler will be done.	Procedure: History and physical exam.; At every study visit, participant's will be asked about their medical history and will have a physical exam.; Other Names: H&P; Procedure: Blood draw.; At each study visit, participants will have an intravenous catheter (IV) placed in one of their veins and blood will be drawn from the IV for study testing.; Other Names: Phlebotomy; Procedure: Pulmonary function testing.; At every study visit, participants will have their lung function assessed. This is done by blowing forcefully at least 3 times into a tube. Testing will be done two times; before and after the use of an Albuterol inhaler.; Other Names: PFTs; Drug: Albuterol inhaler.; At every study visit, participating subjects will take 2 puffs of an Albuterol inhaler after the first set of PFTs, but before the second set of PFTs. There will be at least a 30 minute period after the use of the Albuterol inhaler and the second set of PFTs.; Other Names: Ventolin; Proventil; Proventil-HFA; AccuNeb; Vospire; ProAir
Cystic Fibrosis; Those diagnosed with Cystic Fibrosis (CF) with mutation Delta F508. At every study visit, a history and physical exam (H&P), blood draw, and pulmonary function testing (PFTs) with the use of an albuterol inhaler will be done.	Procedure: History and physical exam.; At every study visit, participant's will be asked about their medical history and will have a physical exam.; Other Names: H&P; Procedure: Blood draw.; At each study visit, participants will have an intravenous catheter (IV) placed in one of their veins and blood will be drawn from the IV for study testing.; Other Names: Phlebotomy; Procedure: Pulmonary function testing.; At every study visit, participants will have their lung function assessed. This is done by blowing forcefully at least 3 times into a tube. Testing will be done two times; before and after the use of an Albuterol inhaler.; Other Names: PFTs; Drug: Albuterol inhaler.; At every study visit, participating subjects will take 2 puffs of an Albuterol inhaler after the first set of PFTs, but before the second set of PFTs. There will be at least a 30 minute period after the use of the Albuterol inhaler and the second set of PFTs.; Other Names: Ventolin; Proventil; Proventil-HFA; AccuNeb; Vospire; ProAir
Without Lung Disease Diagnosis; Those without the diagnosis of AAT Deficiency or CF. At every study visit, a history and physical exam (H&P), blood draw, and pulmonary function testing (PFTs) with the use of an albuterol inhaler will be done.	Procedure: History and physical exam.; At every study visit, participant's will be asked about their medical history and will have a physical exam.; Other Names: H&P; Procedure: Blood draw.; At each study visit, participants will have an intravenous catheter (IV) placed in one of their veins and blood will be drawn from the IV for study testing.; Other Names: Phlebotomy; Procedure: Pulmonary function testing.; At every study visit, participants will have their lung function assessed. This is done by blowing forcefully at least 3 times into a tube. Testing will be done two times; before and after the use of an Albuterol inhaler.; Other Names: PFTs; Drug: Albuterol inhaler.; At every study visit, participating subjects will take 2 puffs of an Albuterol inhaler after the first set of PFTs, but before the second set of PFTs. There will be at least a 30 minute period after the use of the Albuterol inhaler and the second set of PFTs.; Other Names: Ventolin; Proventil; Proventil-HFA; AccuNeb; Vospire; ProAir

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of macrophage function.	From every study participant, we will collect blood from a vein through the placement of an intravenous catheter (IV). We will complete various experiments that will allow us to see how well each participant's macrophage cells are working.	On average, within 30 days from the time the blood is collected.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of the amount of alpha-1 antitrypsin in the blood.	From every study participant, we will collect blood from a vein through an IV.	On average, within 30 days from the time the blood was collected.
Comparison of the amount of an inflammatory marker in the blood, called C-reactive protein.	From every study participant, we will collect blood from a vein through and IV.	On average, within 30 days from the time the blood is collected.
Evaluation of lung function.	Lung function testing will be done on every study participant. This is is done by forcefully blowing into a tube on at least 3 separate occasions. Albuterol, an inhaled medication used to expand lung airways, will be given after lung function testing and then the testing will be repeated after 30 minutes.	On average, within 30 days from the time the testing is completed.

Collaborators and Investigators

• Sponsor: University of Florida
• Investigators: Principal Investigator: Mark Brantly, MD, University of Florida, College of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine

Publications and helpful links

General Publications

• Blank CA, Brantly M. Clinical features and molecular characteristics of alpha 1-antitrypsin deficiency. Ann Allergy. 1994 Feb;72(2):105-20; quiz 120-2. Erratum In: Ann Allergy 1994 Apr;72(4):305.
• Yoshida A, Lieberman J, Gaidulis L, Ewing C. Molecular abnormality of human alpha1-antitrypsin variant (Pi-ZZ) associated with plasma activity deficiency. Proc Natl Acad Sci U S A. 1976 Apr;73(4):1324-8. doi: 10.1073/pnas.73.4.1324.
• Jeppsson JO. Amino acid substitution Glu leads to Lys alpha1-antitrypsin PiZ. FEBS Lett. 1976 Jun 1;65(2):195-7. doi: 10.1016/0014-5793(76)80478-4. No abstract available.
• Lomas DA, Evans DL, Finch JT, Carrell RW. The mechanism of Z alpha 1-antitrypsin accumulation in the liver. Nature. 1992 Jun 18;357(6379):605-7. doi: 10.1038/357605a0.
• Perlmutter DH. Liver injury in alpha1-antitrypsin deficiency: an aggregated protein induces mitochondrial injury. J Clin Invest. 2002 Dec;110(11):1579-83. doi: 10.1172/JCI16787. No abstract available.
• Hidvegi T, Schmidt BZ, Hale P, Perlmutter DH. Accumulation of mutant alpha1-antitrypsin Z in the endoplasmic reticulum activates caspases-4 and -12, NFkappaB, and BAP31 but not the unfolded protein response. J Biol Chem. 2005 Nov 25;280(47):39002-15. doi: 10.1074/jbc.M508652200. Epub 2005 Sep 23.
• Kaufman RJ. Orchestrating the unfolded protein response in health and disease. J Clin Invest. 2002 Nov;110(10):1389-98. doi: 10.1172/JCI16886. No abstract available.
• Oda Y, Okada T, Yoshida H, Kaufman RJ, Nagata K, Mori K. Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation. J Cell Biol. 2006 Jan 30;172(3):383-93. doi: 10.1083/jcb.200507057.
• Seager Danciger J, Lutz M, Hama S, Cruz D, Castrillo A, Lazaro J, Phillips R, Premack B, Berliner J. Method for large scale isolation, culture and cryopreservation of human monocytes suitable for chemotaxis, cellular adhesion assays, macrophage and dendritic cell differentiation. J Immunol Methods. 2004 May;288(1-2):123-34. doi: 10.1016/j.jim.2004.03.003.
• Newman BH. Donor reactions and injuries from whole blood donation. Transfus Med Rev. 1997 Jan;11(1):64-75. doi: 10.1016/s0887-7963(97)80011-9.

Helpful Links

• University of Florida, Division of Pulmonary Medicine, Critical Care & Sleep Medicine

Study record dates

Study Major Dates

• Study Start (Actual): August 9, 2007
• Primary Completion (Estimated): July 20, 2032
• Study Completion (Estimated): July 20, 2033

Study Registration Dates

• First Submitted: April 25, 2013
• First Submitted That Met QC Criteria: May 7, 2013
• First Posted (Estimated): May 10, 2013

Study Record Updates

• Last Update Posted (Actual): August 21, 2023
• Last Update Submitted That Met QC Criteria: August 16, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Alpha-1 Antitrypsin Deficiency; Cystic Fibrosis; Macrophage
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Liver Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Subcutaneous Emphysema; Emphysema; Fibrosis; Cystic Fibrosis; Alpha 1-Antitrypsin Deficiency; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Reproductive Control Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Tocolytic Agents; Albuterol
• Other Study ID Numbers: IRB201501051; 699 (Other Identifier: Shands UF Clinical Research Center); 08-2007 (Other Identifier: University of Florida)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Enrolled subjects may request a copy of their clinical testing done while enrolled in the clinical trial. All other data used for publication purposes will be de-identified.
• IPD Sharing Time Frame: This study is a tissue data bank study and data will not be shared with the public
• IPD Sharing Access Criteria: This is no sharing of data in this tissue banking study, so no share access will be used

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No