Biological Insights from Clinical Trials and Networks
Authors: Victor J. Thannickal, James S. Hagood
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Translational research seeks to bridge the gap between the remarkable progress made in basic science discoveries and their “translation” to improved diagnostics and therapeutics for patients. A bedside-to-bench (and back to the bedside) approach is likely to be more successful than the traditional bench-to-bedside approach; unfortunately, the latter has most often led to failed clinical trials and meant a return to the “drawing board,” and usually it is back to the bench. While our understanding of biology will continue to grow from the essential and vital research conducted at the bench, it is the relevance (to human disease) of the questions asked that will be better informed if one starts this iterative endeavor at the bedside.

In this issue of the Journal (pp. 547–556), Xu and colleagues (1) utilized a bedside-to-bench approach to gain insights into the pathogenesis of pulmonary fibrosis in human subjects with a history of cigarette smoking. Cigarette smoking has been associated with a number of clinical syndromes characterized by distinct, sometimes overlapping, histopathologic and radiologic patterns, including pulmonary fibrosis, emphysema, and combined patterns (2). The reasons for these varied host tissue responses to smoking-induced lung injury are not well understood. Xu and colleagues probed a large cohort of former/active smokers enrolled in the COPDGene study (www.copdgene.org) and discovered that statin use is associated with a higher incidence of interstitial lung abnormalities (ILA) on high-resolution computed tomography after adjustment for relevant covariables, including a history of high cholesterol, coronary artery disease, diabetes, hypertension, and other cardiovascular medications (odds ratio [OR], 1.60; 95% confidence interval [CI], 1.03–2.50; P = 0.04). ILA identified in this cohort included radiologic features more typical of pulmonary fibrosis such as reticular abnormalities and traction bronchiectasis in addition to features commonly associated with inflammatory lung diseases (e.g., ground glass opacities). The risk of ILA in statin users was significantly higher in older subjects and in those taking hydrophilic statins, although the reasons for these important modifiers were not explored. To investigate the association between statins and pulmonary fibrosis, these investigators evaluated the effect of pre-treatment with a hydrophilic statin (pravastatin) on bleomycin-induced pulmonary fibrosis in mice. They demonstrate that statin administration aggravates lung fibrosis in this model in association with enhanced inflammatory cell recruitment, caspase-1 activation, and cleaved IL-1β expression, supporting a role for activation of the NLRP3 inflammasome in mediating this effect; further support for this mechanism is provided by demonstrating that statins enhance NLRP3-inflammasome activation via mitochondrial reactive oxygen species (mtROS) generation in macrophages (Figure 1).



Figure 1.

Schematic of a potential mechanism by which statins may promote pulmonary fibrosis. In a COPDGene cohort of current/former smokers, statin use was found to be associated with a higher risk of interstitial lung abnormalities on high-resolution computed ...



Inflammasome activation is an important aspect of innate immune signaling, and may be a critical link between environmental exposures and fibrotic responses in a number of clinical contexts (3–5). In the lung, inflammasome activation links extracellular danger signaling to activation of fibrotic responses (6), and is known to be critical in environmental lung diseases such as silicosis and asbestosis (3, 4). Although originally described in myeloid cells, it is increasingly clear that components of the inflammasome exist in fibroblasts and can mediate phenotypic alterations associated with fibrogenesis (7). Because lipid signaling is critical to inflammatory responses, statin modulation of inflammasome activation is not unexpected. However, statins are known to have pleiotropic effects on cell signaling independent of cholesterol (8). Statin modulation of the Rho kinases may be particularly relevant for wound healing and fibrotic responses. In fact, statins are known to have the potential to accelerate wound-healing responses (9).

An intriguing finding from this study is the influence of aging on statin-associated pulmonary fibrosis in current/former smokers. In subjects over 65 years old, statin users were more likely to have ILA after adjusting for relevant covariates (OR, 1.96; 95% CI, 1.06–3.61; P = 0.03), an effect that was completely lost in subjects 45 to 55 years old. In fact, there was a trend toward protection from ILA in statin users in this younger cohort (OR, 0.36; 95% CI, 0.07–1.78; P = 0.21). How might age affect the purported fibrotic susceptibility to lung injury in statin users? Does aging influence the macrophage phenotype and promote NLRP3 inflammasome activation? Inflammasome activation has been implicated in other aging-associated disorders (10). Is there a link between senescence of one or more lung cell types (including macrophages) and the potential “metabolic stress” induced by statins/cigarette smoke? Do age-associated epigenetic alterations affect the molecular responses to statins and/or smoking? Is the effect of statins on mitochondrial dysfunction and mtROS generation sufficient to explain this age-associated phenotype? What are the effects of statins on structural lung cells implicated in the fibrotic process such as epithelial cells, endothelial cells, and mesenchymal cells?

The study by Xu and colleagues may well raise more questions than it answers. However, in doing so it creates excellent opportunities to better understand the biology of lung inflammation and fibrosis, aging, and responses to environmental stimuli. It remains to be determined whether the proposed mechanism of NLRP3 inflammasome activation in monocytes/macrophages is sufficient to explain the apparent “priming” effect of statins on cigarette smoke–associated ILA observed in human subjects. It also reinforces the importance of starting at the bedside, and of framing research questions based on clinically relevant, even unexpected, observations. Although clinical observations such as the one made by this study may not immediately impact clinical care (as acknowledged by the authors), they are “hypothesis-generating” and set the stage for more in-depth bench studies that may then be re-tested in human subjects. For example, this study provides a strong rationale for characterizing macrophage activation/phenotypes in patients with distinct clinical syndromes associated with cigarette smoke exposure. In response to a noninfectious injury to the lung, whether activation of specific macrophage phenotypes skews the tissue repair response from emphysema to fibrosis would be of significant interest.

There are now ample opportunities for bedside-to-bench research with the growing number of clinical registries and clinical trial databases—they contain a wealth of critical biological information. To realize the promise of translational research, the need for interactive, interdisciplinary research teams cannot be overemphasized. Initial formulation of basic research questions based on sound clinical observations, and further refined by an iterative and supple approach, will allow us to more rapidly impact the care of our patients.