| Acute and chronic inflammation is a major component of many pulmonary illnesses, including asthma, cancer, and chronic obstructive pulmonary disease (COPD). Normally, inflammation can be fully resolved once the stimulus has been removed (e.g. cigarette smoke, air pollutants, microbial particles). However, in many cases inflammatory responses persist without complete resolution. A new paradigm indicates that the resolution of inflammation is a bioactive process that involves a group of lipid molecules called "specialized pro-resolving lipid mediators" (SPMs). These SPMs, which include resolvins, protectins, maresins and lipoxins, are known to actively antagonize acute inflammatory signaling, to promote resolution of inflammation, and to enable return of homeostasis. Here, we show that the pro-resolving lipid mediator, resolvin D1 (RvD1), plays crucial roles in lung homeostasis and may be a potential treatment for inflammatory lung diseases. In a murine model of acute cigarette smoke-induced lung inflammation, RvD1 not only reduced or attenuated acute lung inflammation, but also shortened the duration of the inflammatory response, thus promoting the resolution of inflammation. Moreover, RvD1 promoted neutrophil efferocytosis and the differentiation of alternatively activated (M2) macrophages, indicating that RvD1 is not immunosuppressive.;In a murine model of chronic cigarette smoke-induced emphysema, RvD1 inhibited smoke-induced airspace enlargement. Furthermore, RvD1-treated animals showed a reduction in chronic inflammation, oxidative stress, and cell death, highlighting the protective effects of RvD1 against chronic cigarette smoke exposure.;An in vitro culture model was utilized to gain a better understanding of the mechanism by which RvD1 modulates pro-inflammatory signaling. In primary human small airway epithelial cells, RvD1 inhibited the production of pro-inflammatory mediators by blocking the phosphorylation of extracellular signal-regulated kinases (ERK)-1 and 2 and nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) p65, a response that is typically elicited by a viral mimetic ligand poly(I:C). Importantly, RvD1 attenuated the phosphorylation of Transforming growth factor beta-activated kinase (TAK)-1, an upstream effector protein that regulates both the MAP-kinase and NF-kappaB pathways. Most importantly, RvD1 attenuated the formation of a poly(I:C)-mediated signaling complex composed of TAK1, TAK1-binding protein (TAB)-1, and tumor necrosis factor (TNF) receptor-associated factor (TRAF)-6. The final result was the inhibition of TAK1 activation.;Overall, these results suggest that RvD1 targets multiple pro-inflammatory signaling pathways and may have significant therapeutic potential in the treatment of complex inflammatory diseases, including pulmonary fibrosis, asthma, and COPD. |
