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The Lung Likes the Little Fella miR-29.

MicroRNAs (miRNAs), a class of small noncoding RNAs that were found at the beginning of this century to distinctly regulate gene expression, have since been dubbed “tiny players with big roles” (1). Biomedical and genetic evidence suggests that one gene can be modulated by more than one miRNA and each miRNA has multiple targets (2). It is estimated that 30–80% of all genes in the human genome are targeted by miRNAs (2). Not surprisingly, over the past decade we have witnessed an exponential growth in the number of publications implicating miRNA aberrations in a diverse number of diseases. Although most of these studies revealed a cell-autonomous mode of action for miRNAs, i.e., by promoting the degradation of target mRNAs or inhibiting their translation, there is ever-increasing evidence that mRNAs engage in nonautonomous activities via intercellular communication through microvesicles (1). There has been a great deal of interest in delineating the pathophysiological roles of miRNAs in the lung and identifying individual miRNAs as therapeutic targets for treating lung diseases (3). miR-29 is one of the many miRNAs that have pleiotropic functions in pulmonary pathologies. In general, miR-29 appears to mediate critical homeostatic functions, as decreased levels of this miRNA have been frequently noted in many respiratory disorders, including idiopathic pulmonary fibrosis (IPF), pulmonary hypertension, and lung cancer (4–7). miR-29 has received much attention in the context of fibrosis due to its effects on directly targeting genes that encode extracellular matrix proteins such as collagens, fibronectin, and elastin (8). As a matter of fact, miR-29 has been shown to be downregulated in mesenchymal cells/fibroblasts from fibrotic lungs (9). As the primary effectors that mediate this pathology, lung fibroblasts appear to be the ideal focal point for examining miR-29’s role in pulmonary fibrosis. Adding to its therapeutic significance, several studies found that increasing pulmonary miR-29 mediated impressive antifibrotic effects in preclinical mouse models of lung fibrosis (10, 11). However, the pathogenesis of many complex diseases, including IPF, cannot easily be reduced to such simplicity. Lung fibrosis is a complicated process that results in aberrant phenotypes of multiple cell types. There have been numerous studies implicating abnormalities of not only lung fibroblasts but also alveolar epithelial cells, immune cells, and even endothelial cells in this disorder (12). In this issue of the Journal, Xie and colleagues (pp. 721–732) provide another example of the complexity of pulmonary fibrosis by delineating the role of alveolar epithelial miR-29 in this disease (13). They found that in addition to lung fibroblasts, miR-29c is downregulated in alveolar epithelial type II (AEC2) cells of fibrotic lungs. Overexpression of miR-29c in an AEC2 line promoted cell proliferation and protected these cells from bleomycin and endoplasmic reticulum stress-induced apoptosis. These activities of miR-29 in AEC2 are deemed pertinent because defects in AEC regeneration due to reduced proliferation and increased apoptosis are critical factors in the pathogenesis of lung fibrosis. Consistent with the observations in in vitro studies, they found that mice with specific overexpression of miR-29 in AEC2 cells were protected from bleomycin-induced lung fibrosis. There was indeed preservation of AEC2s in the lungs of the bleomycin-treated mice, likely as the result of attenuated apoptosis of these cells. Additional strengths of the study by Xie and colleagues include further confirmation of the indispensability of AEC2 miR-29 for apoptotic protection and the clonogenicity of cells from mice harboring a specific ablation of this miRNA in type II cells. However, whether AEC2 miR-29–deficient animals develop worse fibrosis after bleomycin injury was not explored. Nonetheless, this is one of the more complete studies of this topic and provides unequivocal evidence that impaired AEC2 homeostasis plays a key role in the pathogenesis of lung fibrosis. As previously demonstrated, miR-29 expression is also downregulated in the fibroblasts of fibrotic lungs (9). One would predict that the reduction in miR-29 could similarly render these cells more susceptible to apoptosis. However, this reasoning runs up against the current paradigm of apoptosis resistance as a hallmark of lung fibroblasts (14). Interestingly, another study found that miR-29 is proapoptotic in lung fibroblasts (15). It is a paradox that miR-29 chooses to safeguard one cell type while simultaneously annihilating another in the course of lung fibrosis. One plausible explanation is related to the threshold level of apoptosis induction and the molecular mediators constituting the proand antiapoptotic networks in different types of cells. As selective regulation by miRNAs was found to be closely associated with the relative endogenous levels of miRNA targets (16), it is probable that one specific miRNA regulates distinct sets of genes, which leads to completely different and sometimes even opposing effects, similar to the effects of miR-29 in lung fibroblasts and AECs, respectively. This is an intriguing issue that could be addressed by tracing the fate of fibroblasts and AEC2s in mice with conditional deletion of miR-29 in these cells. There is also a growing consensus that fibrosis is a disease of resolution failure after wound repair (14, 17). Expedited fibroblast apoptosis and alveolar epithelial regeneration are believed to be the two key cellular events that eventually lead to lung homeostasis (14). It is also well known that lung fibrosis induced by one-dose bleomycin injury is a self-resolving process, with the lung returning to near-normal architecture within 8–16 weeks after treatment (17). Given the requirement of miR-29 for AEC2 regeneration, it would be interesting to determine whether miR-29 expression is restored during the resolving phase, and whether ablation or overexpression of miR-29 in AEC2 cells would delay or accelerate, respectively, the resolution of lung fibrosis. Finally, regarding miRNA-based therapies, one has to be aware of potential deleterious side effects because of the remarkable potency of miR-29 in inhibiting the production of essential extracellular matrix components, as was previously demonstrated in preclinical animal models (10, 11). This concern is reinforced by a recent study showing that a miR-29 antagonist is actually beneficial for improving atherosclerotic plaque morphology and thus reducing the risks of vascular rupture, acute myocardial infarction, and death (18). The