Abstract
Epithelial-mesenchymal interactions mediated by soluble growth factors determine the evolution of vertebrate lung physiology, including development, homeostasis, and repair. The final common pathway for all of these positively adaptive properties of the lung is the expression of epithelial parathyroid-hormone-related protein, and its binding to its receptor on the mesenchyme, inducing PPARγ expression by lipofibroblasts. Lipofibroblasts then produce leptin, which binds to alveolar type II cells, stimulating their production of surfactant, which is necessary for both evolutionary and physiologic adaptation to atmospheric oxygen from fish to man. A wide variety of molecular insults disrupt such highly evolved physiologic cell-cell interactions, ranging from overdistention to oxidants, infection, and nicotine, all of which predictably cause loss of mesenchymal peroxisome-proliferator-activated receptor gamma (PPARγ) expression and the transdifferentiation of lipofibroblasts to myofibroblasts, the signature cell type for lung fibrosis. By exploiting such deep cell-molecular functional homologies as targets for leveraging lung homeostasis, we have discovered that we can effectively prevent and/or reverse the deleterious effects of these pathogenic agents, demonstrating the utility of evolutionary biology for the prevention and treatment of chronic lung disease. By understanding mechanisms of health and disease as an evolutionary continuum rather than as dissociated processes, we can evolve predictive medicine.
Highlights
Normal lung development is the result of a functionally interconnected series of cell-molecular steps
We began studying the role of parathyroid-hormone-related protein (PTHrP) in lung development because (a) it was expressed in the embryonic endoderm [26], (b) its receptor was present on the adepithelial mesoderm [27], (c) it had been shown to be stretch regulated in the urinary bladder [28] and uterus [29], and distension of the lung was known to be of physiologic importance in normal lung development [30], (d) knockout of PTHrP caused stage-specific inhibition of fetal lung alveolarization in the transition from the pseudoglandular to the canalicular stage [31]
We subsequently discovered that PTHrP stimulated neutral lipid uptake by developing lung fibroblasts (Figure 1, steps 1 and 2), which we chose to call lipofibroblasts [33], by upregulating ADRP (Figure 1, step 2), a molecule previously shown to be necessary for lipid uptake and storage [34] (Figure 1, step 5)
Summary
Normal lung development is the result of a functionally interconnected series of cell-molecular steps This sequence of biologic events has been positively selected for evolutionarily over biologic time and space [1], resulting in optimal gas exchange mediated by alveolar homeostasis [2]. Elsewhere we have suggested that chronic lung disease (CLD) causes simplification of the lung in a manner consistent with the reversal of the evolutionary process [3, 4] By identifying those mechanisms that have evolved under selection pressure for optimal gas exchange [5], we have theorized that we can effectively reverse the deleterious effects of CLD by promoting the evolutionarily adaptive mechanism [6], rather than by just treating the symptoms [7]. The following recounts the essential role of PPARγ in lipofibroblast differentiation and its exploitation for the effective treatment of the preterm lung
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