Functional CT Assessment of Pulmonary Arterial Dysfunction in Smoking Associated Emphysema

Imaging-based metrics have recently played a central role in the quest to identify chronic
obstructive pulmonary disease (COPD) phenotypes, serving to establish homogeneous
sub-populations to aid in genotyping, therapeutic targeting and design and outcomes
assessment. Recent findings in both animals and humans have lead us to believe that CT
derived perfusion (PBF) and mean transit time (MTT) measures within regionally injured lung
parenchyma provide for a functional phenotype of which may be directly tied to the etiology
of the pathologic process leading to emphysema in acentrilobular emphysema susceptible subset
of the smoking population. The primary hypotheses of the proposal are built around the notion
that smokers prone to emphysema have abnormal vasoregulation in that regional hypoxic
pulmonary vasoconstriction (HPV) continues despite regional lung injury. This failure to
block vasoconstriction alters the repair response and leads to tissue destruction in
emphysema susceptible smokers (SS) with abnormal vasoregulation. The normal response to
regional hypoxia is to shunt blood towards better-ventilated regions. However, smoking
induces small scale, regional infiltrates which in turn lead to local hypoxia, HPV would
interfere with defense mechanisms serving to clear the irritant and thus interfere with
mechanisms of repair. The investigators have demonstrated that, in SS subjects with normal
PFTs but CT evidence of early centriacinar emphysema (CAE), there is an increased
heterogeneity of perfusion. This is supportive of the notion that attenuation of
vasoconstriction has failed. Further, the investigators have demonstrated a tight correlation
between quantitative CT evidence of emphysema with reduced lung volume (LV) filling down to
very small amounts of emphysema.

The investigators outline a series of experiments seeking to:

1. link increased pulmonary perfusion heterogeneity in SS subjects to the lung's response
to alveolar oxygenation;

2. establish that the perfusion heterogeneity is reversible;

3. demonstrate that the response to inflammation and not just inflammation itself is a key
factor in the increased heterogeneity.

With any combination of positive outcomes of this study, the investigators will have provided
new insights into disease etiology, serving to provide new targets for disease intervention
and providing the tools needed for assessing outcomes.

Inclusion Criteria:

1. Must be between the ages of 25 and 65.

2. Must be currently smoking at least 1/2 pack/day (confirmed with cotinine level).

3. Must have pulmonary function test (PFT) results that meet the following (there will be
two groups):

Group 1:

- Forced expiratory volume at one second (FEV1)/Forced vital capacity (FVC) > 70%

- Forced Expiratory Flow at 25-75% of predicted(FEF25-75) > 79% of predicted

- FVC greater than 80% of predicted

Group 2:

For subjects with mild lung impairment:

- FEV1>80% of predicted

- FEV1/FVC<0.7

4. Must be able to give informed consent for self.

Exclusion Criteria:

1. Pregnant or breastfeeding females.

2. Body Mass Index (BMI) greater than 32.

3. Weight of greater than 220 pounds (100 kg).

4. Allergies to shell fish, seafood, eggs or iodine.

5. Heart disease, kidney disease or diabetes.

6. Diagnosis of asthma.

7. Usage of any medications that are known to affect the heart or lungs (contraceptives,
anti-depressants, analgesics EXCEPT aspirin, antihypertensives, and medications for
osteoporosis and gastrointestinal diseases will be allowed).

8. Any metal in or on the body between the nose and the abdomen.

9. Any major organ system disease (by judgment of study medical team).

10. A glomerular filtration rate of 60 cc per minute or less.

For the subjects that will receive Sildenafil as part of the study, additional exclusion
criteria are as follows:

1. Nitroglycerin usage or nitrates (in addition to nitroglycerin) and use of
phosphodiesterase 5 (PDE5) inhibitors within the previous 7 days of the study date.

2. Prior history of hypersensitivity to Sildenafil.