A Novel Anti-Inflammatory and Pro-Resolving Role for Resolvin D1 in Acute Cigarette Smoke-Induced Lung Inflammation

Abstract

IntroductionCigarette smoke is a profound pro-inflammatory stimulus that contributes to acute lung injuries and to chronic lung disease including COPD (emphysema and chronic bronchitis). Until recently, it was assumed that resolution of inflammation was a passive process that occurred once the inflammatory stimulus was removed. It is now recognized that resolution of inflammation is a bioactive process, mediated by specialized lipid mediators, and that normal homeostasis is maintained by a balance between pro-inflammatory and pro-resolving pathways. These novel small lipid mediators, including the resolvins, protectins and maresins, are bioactive products mainly derived from dietary omega-3 and omega-6 polyunsaturated fatty acids (PUFA). We hypothesize that resolvin D1 (RvD1) has potent anti-inflammatory and pro-resolving effects in a model of cigarette smoke-induced lung inflammation.MethodsPrimary human lung fibroblasts, small airway epithelial cells and blood monocytes were treated with IL-1β or cigarette smoke extract in combination with RvD1 in vitro, production of pro-inflammatory mediators was measured. Mice were exposed to dilute mainstream cigarette smoke and treated with RvD1 either concurrently with smoke or after smoking cessation. The effects on lung inflammation and lung macrophage populations were assessed.ResultsRvD1 suppressed production of pro-inflammatory mediators by primary human cells in a dose-dependent manner. Treatment of mice with RvD1 concurrently with cigarette smoke exposure significantly reduced neutrophilic lung inflammation and production of pro-inflammatory cytokines, while upregulating the anti-inflammatory cytokine IL-10. RvD1 promoted differentiation of alternatively activated (M2) macrophages and neutrophil efferocytosis. RvD1 also accelerated the resolution of lung inflammation when given after the final smoke exposure.ConclusionsRvD1 has potent anti-inflammatory and pro-resolving effects in cells and mice exposed to cigarette smoke. Resolvins have strong potential as a novel therapeutic approach to resolve lung injury caused by smoke and pulmonary toxicants.

The Protectin PCTR1 Is Produced by Human M2 Macrophages and Enhances Resolution of Infectious Inflammation

“…7,13 Distinctly, PCTR1 at 1 nmol/L did not affect IL-10 levels (data not shown), a known function of PD1 and RvD1. 14,28 In addition, PCTR1 has characteristic tissue regenerative roles and enhances human macrophage phagocytosis and efferocytosis. 6 These results highlight unique biological functions of PCTR1 as a member of the DHA bioactive metabolome.…”

Resolvin D1 Reduces Emphysema and Chronic Inflammation

“…11 The mice were euthanized with Avertin as described in Morphological and Morphometric Analysis. Left lungs were each placed in cold methanol and extracted as described followed by targeted lipid mediatoreSPM profiling using liquid chromatography with tandem mass spectrometry.…”

“…Smoke was generated using 3R4F reference cigarettes (University of Kentucky Reference Cigarette Program) smoked according to the Federal Trade Commission protocol (1 puff per minute of 35-mL volume per cigarette) and diluted with filtered room air using a Baumgartner-Jaeger CSM2072i automated smoking machine (CH Technologies, Westwood, NJ) as previously described. 11,16 The number of cigarettes loaded in the carousel and the flow rate of dilution air were adjusted to give a nominal smoke exposure of 250 mg/m 3 total particulate matter; the mean concentration of these exposures was 265 AE 48 mg/m 3 . Control animals were exposed to filtered room air.…”

“…injection, or vehicle only (80 mice total, 10 mice per group). In our previous study, 11 we determined that 100 ng of ATRvD1 given daily over 4 days was well tolerated and effective in inhibiting acute cigarette smokeeinduced inflammation. We also conducted a pilot study (data not shown) that compared AT-RvD1 100 ng daily to a single 500-ng dose at the beginning of a 4-day acute-inflammation protocol and determined that the single dose was effective for at least 4 days, with no discernable adverse effects.…”

“…Previously, we reported that RvD1 inhibits acute lung inflammation elicited by cigarette smoke exposure and facilitates the resolution of inflammation after smoke exposure by limiting inflammatory cell infiltration and promoting macrophage phagocytosis. 11 Others have shown that RvD1 attenuates LPS-induced and acid-induced acute lung injury, as well as allergic airway inflammation. 11e13 These results suggest that RvD1 plays a role in resolution and homeostasis in the lung and that RvD1 might be used for treating inflammatory lung disease caused by harmful inhaled toxicants and microorganisms.…”