The Regenerative Role of Retinoids in Emphysematous Postnatal Mouse Lungs

Student thesis: Doctoral ThesisDoctor of Philosophy


Debilitating lung disorders such as chronic pulmonary disease (COPD) and
bronchopulmonary dysplasia (BPD) are presently incurable. The World Health
Organization (WHO) predicts that by 2030, COPD will rise to become the third
leading cause of death. Much of the increase in COPD is associated with the
increase in tobacco use and the exposure to smoke combustion from fuel. COPD
includes chronic bronchitis and emphysema. It is caused not only by inhalation of
polluted air, but also by infections as well as genetic predispositions.

To protect the respiratory airways, goblet cells in the bronchiole epithelium produce and secrete a viscous substance known as mucus along with enzymes to breakdown and remove inhaled toxins. Repeated and prolonged exposure to these toxins cause an overproduction of both mucus and enzyme secretion to become uncontrollable.

As a result, the airway epithelium becomes scarred and fibrotic. These enzymes
breakdown the delicate alveolar cell walls creating enlarged alveoli space. Elastic
fibers in these cell walls are also destroyed resulting in a loss of elastic recoil
narrowing the airways thus obstructing airflow. It becomes difficult to obtain enough oxygen into the blood and to remove excess carbon dioxide. These changes lead to a shortness of breath and other symptoms. Unfortunately, the symptoms of COPD cannot be eliminated with current treatment available and the condition inevitably worsens over time. Treatment available might not eliminate symptoms, but they can sometimes slow the progression of the disease.

Transplantation and oxygen therapy are two of the common forms of treatment. The problem with these therapies is that it requires the patient to be relatively healthy, so therefore assessable to few patients. One possible way to treat COPD would be to somehow induce regeneration in these lungs or to impart, self-heal. Unfortunately, adult lung tissue seems incapable of spontaneous repair therefore understanding how to activate repair mechanism would greatly improve the prospects of effective treatments and the prognosis for COPD patients. Previous studies including the use of experimental adult rat model of emphysema has suggested one way to induce lung regeneration is via the endogenous metabolite
of vitamin A, retinoic acid (RA). In the current study, we have described a mouse
model of disrupted alveolar development using a dose-dependent glucocorticoid
steroid, dexamethasone administered postnatally to create serve loss of alveolar
surface area. When RA is induced to these animals as adults the lung architecture is restored to normal. This remarkable effect may be because RA is involved in
alveolar development.

We also provide evidence that RA and its agonists are required for the ongoing maintenance of alveolar structure and function because rats deprived of dietary
retinol lose alveoli and show pathological features of emphysema. Alveolar
regeneration with RA and its agonists may therefore be an important part of a novel therapeutic approach for the treatment of respiratory diseases characterized by reduced gas-exchanging surface areas such as BPD and emphysema.
Date of Award2014
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorPatrick Doherty (Supervisor) & Guy Tear (Supervisor)

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