Source: KANSAS STATE UNIV submitted to
THE ROLE OF VITAMIN A IN PROTECTING THE LUNG AGAINST EMPHYSEMA AND LUNG INFLAMMATION
 
PROJECT DIRECTOR: Baybutt, R. C. Wang, W.
 
PERFORMING ORGANIZATION
HUMAN NUTRITION & FOODS
KANSAS STATE UNIV
MANHATTAN,KS 66506
 
NON TECHNICAL SUMMARY: a)The goal of this research is to provide basic information defining the role of vitamin A in preventing disease.
 
OBJECTIVES: 1) We plan to confirm and establish that vitamin A protects the lung and other organs against injury when exposed to cigarette smoke. 2) We plan to evaluate different all-trans retinoic acid concentrations and different times of administration. 3) We plan to define which form of vitamin A is most effective in protecting the lung against inflammation and emphysema. 4) We plan to define the mechanism by which vitamin A protects against inflammation and emphysema. For defining the role of vitamin A in inflammation, we will determine how vitamin A alters the lung macrophage cytokine profile in cigarette smoke-exposed rats by using microarray analysis followed by enzyme immunoassays as means for determining the mRNA and its subsequent protein for the specific cytokines that are affected. To evaluate the role of vitamin A in protecting against emphysema, we will determine a time course for mRNA expression for elastin and the amount of elastin mRNA and protein that are produced in response to retinoic acid. Retinoic acid has been found to increase elastin mRNA and protein in skin fibroblasts. We also plan to develop a microarray for determining the differential expression of the nuclear retinoic acid receptor in response to cigarette smoke with or without supplemented retinoic acid (vitamin A). 5) We plan to use a cell culture model for studying the effects of cigarette smoke and its interaction with other nutrients., in particular vitamin A, on function of type II pneumocytes.
 
APPROACH: By understanding the basic mechanisms, we can then use this information to apply to a clinical setting which would impact our clientele. Below are listed the research objectives along with the expected outcome with its economic, social, and/or environmental impact. 1) We plan to restore toxin induced depleted vitamin A by supplementing with retinoic acid (an active form of vitamin A) to evaluate its protective effect. We will also plan to compare this beneficial effect of vitamin A in a monocrotaline model of lung inflammation and emphysema. 2) We will also use different doses of the cigarette smoke and different lengths of time of exposure. 3) We plan to define which form of vitamin A is most effective in protecting the lung against inflammation and emphysema. 4) In particular, we will evaluate the effect of all-trans retinol, 11-cis retinal, all-trans retinoic acid, 9-cis retinoic acid, and 13-cis retinoic acid.
 
CRIS NUMBER: 0196001 SUBFILE: CRIS
PROJECT NUMBER: KS636 SPONSOR AGENCY: NIFA
PROJECT TYPE: HATCH PROJECT STATUS: TERMINATED MULTI-STATE PROJECT NUMBER: (N/A)
START DATE: Jul 1, 2003 TERMINATION DATE: Jun 30, 2007

GRANT PROGRAM: (N/A)
GRANT PROGRAM AREA: (N/A)

CLASSIFICATION
Knowledge Area (KA)Subject (S)Science (F)Objective (G)Percent
702384010105.120%
723384010102.380%

CLASSIFICATION HEADINGS
KA723 - Hazards to Human Health and Safety
KA702 - Requirements and Function of Nutrients and Other Food Components
S3840 - Laboratory animals
F1010 - Nutrition and metabolism
G5.1 - Ensure Access to Nutritious Food
G2.3 - Provide Risk Management and Financial Tools


RESEARCH EFFORT CATEGORIES
BASIC 50%
APPLIED 50%
DEVELOPMENTAL (N/A)%

KEYWORDS: vitamin a; emphysema; lungs; disease prevention; nutrient disease relations; inflammation; pulmonary diseases; nutrient function; human health; human nutrition; smoke; smoking; cigarettes; cytokines; mechanism of action; rats; macrophages; animal models; rna m; gene expression; elastin; retinoic acid; receptors; metabolic regulation; dosage; exposure

PROGRESS: Jan 1, 2006 TO Dec 31, 2006
We have sufficient data and evidence to suggest that vitamin A protects the lung against emphysema and other lung diseases (e.g. cancer) due to the environmental toxins monocrotaline or cigarette smoke. We have carried out experiments in vitro and in vivo to demonstrate this. We previously found that molecular markers for cancer (RAR alpha, c-Jun, c-Fos, proliferating cellular nuclear antigen (PCNA)) and cell cycle markers (cyclin E and D1) are elevated in a dose dependent fashion in response to increasing exposure to cigarette smoke (1, 2, and 3 packs per day). These increases in proliferation factors corresponded to a depletion of vitamin A (retinoic acid) content of the lung and decreased expression of RARbeta, a tumor suppressor gene. These data indicate that vitamin A depletion, induced by cigarette smoking, might decrease RAR and subsequently increase c-Jun to increase cell proliferation and cell cycle. In a subsequent study we cast a larger net using a selective microarray to investigate which mRNAs and ultimately proteins were regulated by vitamin A in response to injury. The purpose of the use of the microarray was to look at a set of cancer-related genes and determine which gene expressions were decreased by retinoic acid. Cell division was promoted with smoking and the smoke-induced increase in cell division markers were prevented to some degree by vitamin A. Vitamin A promoted apoptosis (programed cell death) and smoking inhibit it. We are continuing to analyze and summarize the data. We presented some preliminary findings at the Experimental Biology Meeting in 2006. This microarray work was also presented as part of a PhD dissertation. The other experiments presented in the dissertation were vitamin A and its impact on proliferative proteins and on bone mineral content and density.

IMPACT: 2006-01-01 TO 2006-12-31 Cigarette smoke has been found to deplete vitamin A levels in the lung of rats. The health consequences of this are not fully understood, however, the environment that is set up by smoking cigarettes is one that promotes cell division and proliferation, favoring cancer development. Can providing adequate vitamin A to replenish that which is depleted by cigarette smoke overcome some of the deleterious effects of smoking? Increasing evidence from our lab suggests that this may be true.

PUBLICATION INFORMATION: 2006-01-01 TO 2006-12-31
Published Abstracts: Xue,Y, Wang, W, and Baybutt, RC. Microarray analysis of lung cancer-related signaling pathways in cigarette smoke-exposed rats with/without vitamin A supplementation. FASEB 20:A1013, 2006.

PROJECT CONTACT INFORMATION
NAME: Baybutt, R. C.
PHONE: 785-532-0169
FAX: 785-532-1674