Is a regenerative approach viable for the treatment of COPD?

Abstract

Degenerative lung diseases such as chronic obstructive pulmonary disease (COPD) are common with huge worldwide morbidity. Anti-inflammatory drug development strategies have proved disappointing and current treatment is aimed at symptomatic relief. Only lung transplantation with all its attendant difficulties offers hope of cure and the outlook for affected patients is bleak. Lung regeneration therapies aim to reverse the structural and functional deficits in COPD either by delivery of exogenous lung cells to replace lost tissue, delivery of exogenous stem cells to induce a local paracrine effect probably through an anti-inflammatory action or by the administration of small molecules to stimulate the endogenous regenerative ability of lung cells. In animal models of emphysema and disrupted alveolar development each of these strategies has shown some success but there are potential tumour-inducing dangers with a cellular approach. Small molecules such as all-trans retinoic acid have been successful in animal models although the mechanism is not completely understood. There are currently two Pharma-sponsored trials in progress concerning patients with COPD, one of a specific retinoic acid receptor gamma agonist and another using mesenchymal stem cells.

Figure 1

Varying forms of endogenous cells found in the lung, which can proliferate after lung injury including the more classical stem cells (redrawn from Rawlins and Hogan, 2006). Throughout the proximal lung are K-14 +ve basal cells (green), which give rise to Clara cells and ciliated cells after injury. Also in the proximal lung are cells in the ducts of the submucosal glands (purple), which can take up BrdU. In the distal lung there are neuroendocrine cells (pink), which can proliferate but do not give rise to other cell types. Adjacent to neuroendocrine bodies are variant Clara cells (blue), which can give rise to more Clara cells and ciliated cells after injury. At the bronchioalveolar junction are bronchioalveolar stem cell (BASCs) (yellow), which can give rise to ciliated cells, Clara cells and type II cells. In the alveoli are type II cells (red), which give rise to type I cells. Type I cells in the alveoli, and ciliated cells and Clara cells in the proximal and distal lung are uncoloured.