The Role of PPARy in Pulmonary Tissue Homeostasis and Ageing

Tissue-specific stem cells have already been identified for many tissues. In the lungs alveolar type II cells (ATII), are essential for the development and repair of the gas- exchange surface. Surfactant protein production and survival of ATII cells is supported by lipofibroblasts, and their differentiation is PPARy-dependent [68]. The process is strongly influenced by the Wnt/p-catenin signaling pathway: in the case of PPARy-dominance lipofibroblast differentiation is skewed towards myofibroblast differentiation that does not support ATII replenishment. With age PPARy expression decreases, while Wnt secretion increases. Consequently, stem cell capacity to renew the ATII cell pool decreases and as does pulmonary regenerative capacity shrink with age that renders the lungs more vulnerable to various diseases and conditions [6]. However, reinforcing PPARy activity through TZD administration

Fig. 6.3 Conditions related to diminished PPARy activity (left) outweigh those linked with elevated PPARy activity (right) in the lungs

has been shown to induce myofibroblast transdifferentiation into lipofibroblast cells. This may replenish the stem cell pool of pulmonary tissues, potentially counteracting the pro-ageing decrease of PPARy activity observed during physiological senescence [69].

It is currently accepted that alterations in pulmonary PPAR profile, more precisely loss of PPARy activity, can lead to inflammation, allergy, asthma, COPD, emphysema, fibrosis, and cancer (Fig. 6.3) [70]. Since it has been reported that PPARy activity decreases with age, this provides a possible explanation for the increasing incidence of these lung diseases and conditions in older individuals [6]. The significance of maintaining PPARy-activity in the lungs has led to research looking for potential novel biomarkers and therapeutic targets. A simplified approach would postulate TZDs as universal adjuvants for the treatment of various lung diseases and age-related pulmonary conditions. However, one must keep in mind that TZDs have a history in human therapy being used for the oral treatment of type 2 diabetes (PPARy decreases insulin resistance) and certain TZDs have been restricted due to an increased incidence of cardiac events [71]. For pulmonary treatment this risk may be circumvented if nebulized TZDs are applied that maximize local efficiency and minimize systemic side effects [72]. Nevertheless, there are also reports on the potential harmful effects of TZDs with respect to lung cancer cell dissemination (not formation) by rendering the pulmonary micro-environment permissive for tumour cell survival [73].

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