Effect of Losartan on Airway Mucociliary Dysfunction in Patients With COPD and Chronic Bronchitis

Investigator's preliminary data show that TGF-ß1 and cigarette smoke exposure decrease BK
activity and cause airway surface liquid (ASL) volume depletion and losartan partially
rescues BK channel function leading to increased ASL volume and ciliary beat frequency (CBF)
in airway epithelial cells exposed to smoke.

Therefore the investigators propose that smoke exposure, via TGF-ß1 production, leads to
apical BK channel dysfunction to cause ASL volume depletion and mucociliary dysfunction in
smokers and ex-smokers with COPD. Clinically used Angiotensin II Receptor Blockers (ARBs) are
known to inhibit TGF-ß signaling and present a "low-hanging-fruit" approach (medication
already in clinical use) for intervention in COPD. In a murine model, losartan has previously
been shown to attenuate cigarette smoke-induced lung injury and to rescue lung architecture.

The long-term goal of this study is evaluate the effect of currently available and clinically
useful TGF-ß1 signaling inhibitors (ARBs) on mucociliary function in individuals with
smoke-associated airway diseases, such as chronic bronchitis and COPD.

To test that hypothesis, subjects with COPD will be given four weeks of 50 mg of losartan
daily and consequently an additional four weeks of 100 mg of losartan (divided in two doses
of 50 mg twice daily).

Inclusion Criteria:

1. Fulfill one of the group definitions above

2. Age between 35 and 75 years old

3. Clinical diagnosis of chronic bronchitis, defined as productive cough for at least 3
months per year for at least two consecutive years

4. Stable maintenance of all current medication therapy for 3 months, including ARBs for
treated groups

Exclusion criteria

1. Current therapy with ACE inhibitor,or Intolerance to ARB

2. Women of child bearing potential

3. Current use of nonsteroidal antiinflammatory drugs or potassium supplementation,
treatment with aliskiren, anticoagulation

4. COPD exacerbation requiring treatment within 6 weeks of the screening visit

5. Oral corticosteroid use within 6 weeks of the screening visit

6. Significant hypoxemia (oxygen saturation <90% on room air), chronic respiratory
failure by history (pCO2 > 45 mmHg) and forced expiratory volume in 1 second (FEV1)
below 40%, clinical evidence of cor pulmonale

7. Untreated arterial hypertension (systolic blood pressure >140 mm Hg, diastolic blood
pressure > 90 mm Hg)

8. Ability to understand and willingness to sign consent documents

9. Blood pressure less than 100 mm Hg systolic or 70 mm Hg diastolic while standing at
the screening visit

10. Cardiac, renal, hepatic (LFTs > 3x normal upper limit), neurological, psychiatric,
endocrine or neoplastic diseases that are at the discretion of the investigator, to
interfere with participation in study

11. History of renal artery stenosis

12. Concomitant airway disorders other than COPD and chronic bronchitis, such as
bronchiectasis and asthma (history and reversible airflow obstruction by American
Thoracic Society (ATS) criteria)

13. History of pulmonary malignancies, and any other malignancies in the last 5 years

14. History of thoracic surgery.

15. Acute pulmonary exacerbation within 6 weeks from the Screening Visit.

16. Subjects with no airflow obstruction by spirometry but with a decrease in diffusing
capacity of lung for carbon monoxide(DLco) possibly indicating emphysema.

17. Significant exposure to environmental tobacco smoke or atmospheric or occupational
pollutants

18. Urine pregnancy positive test at the Screening Visit.