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ACEing Radiation Protection:
The Role of ACE Inhibitors in Mitigation of Radiation Damage
BROOKFIELD CENTRAL HIGH SCHOOL
Max Czechowski, Adam El-Meanawy, Jialuo Gao, Jason Hubler, Tahmid Iqbal, Tarun Jella, Eugene Kim, Raga Komandur, Corey Li, Serena Nicoll, Hafsa Shereen, Zheng Yan, and Alice Zheng
Teacher: Louise Thompson Mentor: Meetha Medhora, PhD, Medical College of Wisconsin
Introduction
•Lungs are very sensitive to radiation: doses of radiation to cancer patients are limited by the damage to the normal lung surrounding a tumor.
•Radiation from a nuclear accident or terrorist event can injure sensitive lung tissue: can we find an effective treament?
•Research using angiotensin converting enzyme (ACE) inhibitors to mitigate radiation lung injury is ongoing at the Medical College of Wisconsin.
•Our goal was to build a model of ACE bound to the inhibitor lisinopril, to help determine the molecular mechanism of mitigation of radiation lung injury.
Why We Need to Mitigate Radiation Damage:
The 9/11 attacks on the Twin Towers resulted in the deaths of
thousands. Since the calamity, fighting terrorism has been a major
priority for the United States. The rising global threat of radiological terrorism has caused great concern regarding the protection of
Americans and the US. The US Government has asked the NIH
to organize research to study the mechanisms of radiation injuries
and potential ways to mitigate these effects, as well as to develop
protocols for identifying irradiated victims. Our mentor is one of the
many researchers who are contributing to the advancement of irradiation protocols and treatments.
High dose radiation to the thorax causes major morbidity. (see
Figure 1)The angiotensin-converting enzyme inhibitors, or ACE inhibitors, mitigate the radiation damage to the lungs. A significant effect from radiation damage is delayed pulmonary fibrosis. Without
ACE inhibitors, radiation damage causes excessive collagen production in the alveolar walls which disrupts the gas exchange in the
lungs, inhibiting respiration. Angiotensin I converts to angiotensin
II, which normally binds to receptors on fibroblasts in the lungs to
initiate the pathway leading to the production of collagen. The inhibitors disable ACE from converting angiotensin I to angiotensin II,
which in turn prevents collagen over-production. (See pathway diagram to right.)
ACE Inhibitors mitigate radiation induced morbidity
Lisinopril-ACE Inhibition Pathway
Figure 2*: The diagram to the right shows the pathway leading from
Angiotensinogen to Angiotensin I and II, using ACE, and the presence or abscence of collagen in the lungs.
A
B
C
Angiotensinogen
Renin
Catalyzes
Conversion
of Angiotensinogen
to Angiotensin
D
F
E
Angiotensin I
Lisinopril
ACE
50 µm
inhibits ACE
Converts
Angiotensin
I to Angiotensin II
Figure 4 **: These images are Masson’s trichrome stained slides
of rat lungs after 7 months of WTI. Figure A shows lungs of rat
without irradiation; B: 13 Gy WTI without drug; C: 13 Gy WTI with
captopril; D: 13 Gy WTI with enalapril; E: 13 Gy WTI with fosinopril. B shows thickened walls of alveoli where collagen (colored
blue) has been deposited.
Angiotensin II
causes buildup of
collagen in alveolar
interstitial space
ACE +
Lisinopril
does not
convert Angiotensin from I
to II
Collagen, a
marker of Fibrosis,
stained in blue
ACE Bound to Lisinopril
Figure 1 **: This Kaplan-Meier plot shows the percent morbidity of
rats days after 13 Gy whole thoracic irradiation (WTI). Rats were
treated with the ACE inhibitors enalapril, captopril, or fosinopril. The
rats treated with captopril demonstrated a lower percent morbidity.
Unlike captopril and enalapril, fosinopril does not reduce morbidity.
Numbers in parentheses represent number of surviving animals at
80 days.
ACE Inhibitors Reduce Collagen in the Lungs
Figure 3*: Lisinopril, colored yellow,
bound to Angiotensin Converting Enzyme (ACE) at its active site composed
of Tyr224, His353, Ala354, His383,
Glu384, His387, Glu411, Lys511,
His513, Tyr520, Arg522, and Tyr523. Active site amino acids are colored CPK.
The beta sheets are colored orchid,
while the alpha helices are colored midnight blue. The chlorine atom at the active site is colored lime, and the zinc
atom is colored green. The unconstructed backbone is colored pale goldenrod.
The Promise of ACE Inhibitors
A
B
Figure 5 **: A: Four to seven months after 13 Gy whole thoracic irradiation (WTI), newly synthesized collagen in the rats’ lungs
were measured. Rats exposed to 13 Gy WTI experienced an increase of collagen in the lung compared to untreated rats.
B: Amount of newly synthesized collagen at 7 months post WTI
and drug treatment. Rats treated with ACE inhibitors showed less
collagen synthesis than WTI rats with no drug. “N” represents
sample size.
Citations:
PDB ID: 1O86
*R. Natesh, S. L. U. Schwager, E. D. Sturrock & K. R. Acharya. (2003). Crystal Structure of the Human Angiotensin-converting Enzyme-Lisinopril Complex. Letters to Nature 421: 551 – 554
**L. Kma, F. Gao, B. L. Fish, J. E. Moulder, E. R. Jacobs, and M. Medhora.(2012). Angiotensin Converting Enyme Inhibitors Mitigate Collagen Synthesis Induced by a Single Dose of Radiation to the Whole Thorax. J. Radiat. Res., 53: 10 - 17​
“The SMART Team Program is supported by the National Center for Advancing Translational Sciences, National Institutes
of Health, through Grant Number 8UL1TR000055. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.”
The mentor Meetha Medhora was supported by the National Institute of Allergy & Infectious Diseases at the National Institutes of Health (NIH/NIAID) awards RC1AI81294&S1, R01AI101898 and U01AI107305.
•The potential of ACE inhibitors such as lisinopril to mitigate lung damage following high-dose radiation exposure was analyzed. Findings show that ACE inhibitors are capable of
reducing morbidity when treatment is given after the radiation dose.
•Our mentor’s study shows that ACE inhibitors have a statistically significant effect in minimizing collagen buildup in lung tissue following irradiation.
•ACE inhibitors show promise as viable treatments for individuals exposed to high doses of radiation by reducing long term damage to the lungs.
•Further studies regarding this topic will benefit victims of nuclear accidents and terrorism. Patients undergoing radiotherapy for cancer can also benefit from this possible treatment.
•We have designed a model of ACE with lisinopril bound in the active site to help understand the molecular mechanism of mitigation.