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

Alpha-1 Antitrypsin Deficiency Clinical Trial

Official title:

The Role of Conformational Diseases on Macrophage Function

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01851642
• Other study ID #: IRB201501051
• Secondary ID: 69908-2007
• Status: Recruiting
• Start date: August 9, 2007
• Est. completion date: July 20, 2033

Study information

• Verified date: August 2023
• Source: University of Florida
• Contact: Jesse R West, RN, CCRC
• Phone: 352-273-8666
• Email: jesse.west[@]medicine.ufl.edu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 220
• Est. completion date: July 20, 2033
• Est. primary completion date: July 20, 2032
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• AAT Deficiency
• AATD
• Alpha 1-Antitrypsin Deficiency
• Alpha-1 Antitrypsin Deficiency
• Cystic Fibrosis
• Cystic Fibrosis (CF)
• Fibrosis

Intervention

Procedure:
• History and physical exam.
At every study visit, participant's will be asked about their medical history and will have a physical exam.
• 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.
• 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.

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.

Locations

Country	Name	City	State
United States	Shands at the University of Florida	Gainesville	Florida

Sponsors (1)

Lead Sponsor	Collaborator
University of Florida

Country where clinical trial is conducted

United States, 

References & Publications (10)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	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.
Secondary	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.

External Links

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