Generation of a Chronic Obstructive Pulmonary Disease Model in Mice by Repeated Ozone Exposure

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and lung parenchymal destruction. It has a very high incidence in aging populations. The current conventional therapies for COPD focus mainly on symptom-modifying drugs; thus, the development of new therapies is urgently needed. Qualified animal models of COPD could help to characterize the underlying mechanisms and can be used for new drug screening. Current COPD models, such as lipopolysaccharide (LPS) or the porcine pancreatic elastase (PPE)-induced emphysema model, generate COPD-like lesions in the lungs and airways but do not otherwise resemble the pathogenesis of human COPD. A cigarette smoke (CS)-induced model remains one of the most popular because it not only simulates COPD-like lesions in the respiratory system, but it is also based on one of the main hazardous materials that causes COPD in humans. However, the time-consuming and labor-intensive aspects of the CS-induced model dramatically limit its application in new drug screening. In this study, we successfully generated a new COPD model by exposing mice to high levels of ozone. This model demonstrated the following: 1) decreased forced expiratory volume 25, 50, and 75/forced vital capacity (FEV25/FVC, FEV50/FVC, and FEV75/FVC), indicating the deterioration of lung function; 2) enlarged lung alveoli, with lung parenchymal destruction; 3) reduced fatigue time and distance; and 4) increased inflammation. Taken together, these data demonstrate that the ozone exposure (OE) model is a reliable animal model that is similar to humans because ozone overexposure is one of the etiological factors of COPD. Additionally, it only took 6 - 8 weeks, based on our previous work, to create an OE model, whereas it requires 3 - 12 months to induce the cigarette smoke model, indicating that the OE model might be a good choice for COPD research.

Small-Airway Dysfunction is Involved in the Pathogenesis of Asthma: Evidence from Two Mouse Models

“…Ozone exposure has been shown to disrupt largeairway function in mice. 9,19,20 Similarly, we have shown that ozone exposure can induce a decline in FEV50.…”

“…Ozone exposure has been shown to disrupt large-airway function in mice. 9 , 19 , 20 Similarly, we have shown that ozone exposure can induce a decline in FEV50. Furthermore, in the present study, we emphasized the impairment of small-airway function in mouse models of asthma.…”

liver X receptors inhibit pulmonary inflammation and airway remodeling induced by ozone exposure in mice

“…The H&E sections were observed under a 200× magni cation optical microscope, and 10 peripheral visual elds were randomly taken from each section. The images of the sections were opened in Photoshop, a cross line was drawn through the positive center of the image (avoiding the elds of airways and vessels as much as possible), the number of alveolar spaces (n) that passed through these two lines were counted, and the total length of the cross line (L) was measured, which was calculated using the formula, Lm = L / N. The value represents the average alveolar diameter, re ects the degree of alveolar damage [16].…”

When Enough Is Enough: Decision Criteria for Moving a Known Drug into Clinical Testing for a New Indication in the Absence of Preclinical Efficacy Data

“…42,43 In a recent development, researchers have even generated a new COPD mouse model by exposing mice to high levels of ozone. 44 All of these methods are increasing in accuracy and precision and are valuable in many contexts. However, it is also known that the methods to generate the disease model will, by their very nature, change the course of the disease, not just in onset, but in terms of features and phenotypes, progression, and lethality, with unknown effects on eventual generalizability, or lack thereof, to the corresponding human disease.…”