Chronic obstructive pumonary disease (COPD) is a major health issue characterized by constant alveolar destruction and airway inflammation caused by noxious particles (allergens) or gases (smoke). Alveolar epithelial cells are the major targets in the lung under various oxidant stimuli, therefore alveolar epithelial injury is thought to be a critical process in the pathogenesis of COPD.
Non-GLP compliant. The study is generally used in discovery-phase preclinical research.
Purpose of the Study
To induce COPD in a rodent model and assess the efficacy of new compounds
- Adult male Sprague-Dawley will be group-housed in normobaric, normoxic ventilated cages.
- LPS intratracheal instillation at Days 1 and 15.
- Exposure to smoke from 6 cigarettes twice a day, 5 days a week during 2 months.
- Group 1. Healthy animals (6 rats)
- Group 2. COPD animals with vehicle (8 rats)
- Group 3. COPD animals with test article (8 rats)
COPD will be induced in rats by intratracheal instillation of LPS followed by exposure to cigarette smoke.
Respiratory function will be assessed weekly by whole-body plethysmography. At each time point, breathing frequency (Bf), tidal volume, and enhanced pause (Penh) will be recorded, reflecting the changes in the waveform of the box pressure signal from both inspiration and expiration, related to early and late expiration.
Blood can be drawn at different time points for compound and cytokines plasma level quantification. Blood volumes will be limited to 800 µL per week to avoid hypovolumia.
- Whole-body plethysmograph (respiratory function; pulmonary resistance (PenH); sneezing);
- Changes in cytokine levels and cell counts measured in plasma and BALF (IL6, IL8 and TNF-a);
- Changes in mean arterial pressure, and heart rate (HR);
- O2 saturation, ECG intervals;
- Ventilation pressure, volume, frequency; and
- Semi-quantitative and clinical histological analysis based on pulmonary emphysema and vascular remodeling performed independently by two pulmonary histopathologists.
- One week to finalize the protocol/formulation;
- In vivo experimental phase: 54 days (weekly preliminary updates);
- In vitro experimental phase: 14 days for the cytokine quantification and BALF flow cytometry; and
- In vitro experimental phase: 3 weeks for histopathological analysis following collection of the samples.
- Non-audited report 4 weeks following the last measurement. This report will include all functional data as well as cytokine levels.
- Non-audited histological report 21 days following the last measurement.