Is a regenerative approach viable for the treatment of COPD?

British Journal of Pharmacology



Matthew Hind1 and Malcolm Maden2

1Royal Brompton Hospital and National Heart and Lung Institute, Imperial College, Dovehouse St, London, UK, and 2Department of Biology & UF Genetics Institute, Bartram Hall, University of Florida, Gainesville, FL, USA



 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-transretinoic 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.


The emphysema component of COPD results in destruction of alveoli distal to the terminal bronchiole and so any regen- erative therapies must result in the development of new alveoli. While this hope may sound a difficult and perhaps an unattainable goal it is important to bear in mind that the adult alveolus is much more dynamic structure than what is commonly envisaged – in rodents and perhaps in humans too, alveoli can be lost and readily reformed under certain conditions. The discovery of regenerative therapies is concen- trated on two broad strategies – one, adding differentiated stem cells to replace the missing tissue, and two, inducing the endogenous stem cells to proliferate and differentiate into the missing tissue in situ. In the former strategy, ES cells differentiated into type II pneumocytes or using type II cells themselves have been shown to engraft after intratracheal administration and to some degree, repair fibrosis in animal studies. But this approach may have clinical problems either with rejection, the appearance of teratomas from undifferen- tiated ES cells or ethical issues related to the derivation of the ES cells. Adult MSCs from bone marrow would circumvent all of these problems but they seem to engraft only in very low numbers when applied intravenously, although in animal models lung recovery from injury has been seen. Their posi- tive effect may not be related to actual cellular engraftment but the fact that they can have inhibitory influences on immune cells and inflammatory cytokines. However, prob- lems with this approach include the appearance of sarcomas in the lung and the induction of fibrosis, which may worsen any disease. In the future it may be possible to generate a patient’s own IPS cells from skin fibroblasts and differentiate them into type II cells for intratracheal transplantation and perhaps seed these onto engineered scaffolds to improve the structural basis for engraftment, which is an often ignored aspect of tissue regeneration in the lung. One current human trial using this strategy uses bone marrow derived MSCs for patients with COPD.

The second strategy focuses on understanding the signals involved in regulating endogenous stem cells, of which there are several types in the lung. The type II cell is the one involved in alveolar regeneration and several molecules have been shown to induce some degree of regeneration in animal studies including retinoids, oestrogen, adrenomedullin, HGF and statins. The only other current human trial for patients with COPD concerns the use of one of these compounds, a retinoic acid receptor gamma agonist, and the result of this and the MSC trial are eagerly awaited.


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