Endogenous expression pattern of resolvin D1 in a rat model of self-resolution of lipopolysaccharide-induced acute respiratory distress syndrome and inflammation

https://doi.org/10.1016/j.intimp.2014.09.001Get rights and content

Highlights

  • We establish a rat model of self-resolution of LPS-induced ARDS and inflammation.

  • We examine the dynamic variation profile of endogenous RvD1 as well as the resolution process of ARDS inflammation.

  • RvD1 may possess anti-inflammatory properties.

  • RvD1 supplementation should accelerate the process of inflammation resolution.

Abstract

Resolvin D1 (RvD1), an endogenous lipid mediator derived from docosahexaenoic acid, has been reported to promote a biphasic activity in anti-inflammatory response and regulate inflammatory resolution. The present study aimed to determine the endogenous expression pattern of RvD1 in a rat model of self-resolution of lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS) and inflammation. The ARDS model was induced by administrating LPS (2 mg/kg) via tracheotomy in 138 male Sprague–Dawley rats. At specified time points, lung injury and inflammation were respectively assessed by lung histology and analysis of bronchoalveolar lavage fluid and cytokine levels. The expression of endogenous RvD1 was detected by high performance liquid chromatography and tandem mass spectrometry. The results showed that histological lung injury peaked between 6 h (LPS6h) and day 3, followed by recovery over 4–10 days after LPS administration. Lung tissue polymorph nuclear cell (PMN) was significantly increased at LPS6h, and peaked between 6 h to day 2. The levels of interleukin (IL)-6 and IL-10 were significantly increased at LPS6h and remained higher over day 10 as compared to baseline. Intriguingly, the endogenous RvD1 expression was decreased gradually during the first 3 days, followed by almost completely recovery over days 9–10. The finding indicated that endogenous RvD1 underwent a decrease in expression followed by gradual increase that was basically coincident with the lung injury recovery in a rat model of self-resolution LPS-induced ARDS and inflammation. Our results may help define the optimal therapeutic window for endogenous RvD1 to prevent or treat LPS-induced ARDS and inflammation.

Introduction

Inflammation plays a key role in the pathogenesis of acute respiratory distress syndrome (ARDS). The resolution of inflammation is a central component of host defense and the return of tissue to homeostasis. Many of the current therapies for inflammatory diseases focus on blocking the initiating or amplifying mediators of inflammation. Although this strategy has been beneficial in some clinical conditions, there remain substantial unmet clinical needs for common inflammatory lung diseases, including ARDS. Rather than blocking early or selected pro-inflammatory mediators, an alternative therapeutic strategy might emphasize mimetics of lipoxins (LXs), cyclopentenone prostaglandins (cyPGs), resolvins, protectins, or other natural counter-regulatory molecules that accelerate resolution of inflammation [1], [2].

Resolvin D1 (RvD1), an endogenous lipid mediator derived from docosahexaenoic acid, has been shown to promote a biphasic activity in anti-inflammatory response and regulate inflammatory resolution [3], [4]. RvD1 executes its pro-resolving actions within human tissues via its specific interaction with G protein-coupled receptors (GPCRs) ALX and GPR32 [5], [6]. Interestingly, RvD1 exerts specific bioactivities on human polymorph nuclear cell (PMN) and monocytes [7], namely reduction of PMN activation. RvD1 reduces tumor necrosis factor alpha (TNF-α), interleukin 17 (IL-17), interleukin 13 (IL-13) and histamine-stimulated conjunctival goblet cell secretion, and enhances the apoptosis of macrophage [8], [9] Besides, RvD1 can block adhesion molecule integrin β-2 expression, which would inhibit PMN chemotaxis and infiltration and therefore relieve acute inflammation response [5], [10], [11]. Although extensive studies have demonstrated the beneficial effects of RvD1 in pathological states of inflammation and ARDS [12], [13], the dynamic change of endogenous expression of RvD1 was unclear during the process of ARDS.

Therefore, in the study, we explored the patterns of endogenous of RvD1 using high performance liquid chromatography and tandem mass spectrometry in the resolution process of ARDS was induced by tracheal inhalation of lipopoysaccharide (LPS) with the purpose to facilitate the identification of optimal therapeutic window to promote endogenous RvD1.

Section snippets

Reagents

Lipopolysaccharide (LPS, Escherichia coli, O55:B5), resolvin D1 (RvD1) and prostaglandinE1 (PGE1) were purchased from Sigma (St. Louis, MO, USA). Pentobarbital sodium was acquired from Google biological company (PR China). Hexane and methyl formate (HPLC) were acquired from Tianjin biological reagent company (PR China).

Animals

Six-to-eight-week-old male Sprague–Dawley rats (weight range 200 to 300 g, provided by Hunan SJA Laboratory Animal Co. Ltd.) were housed in isolation cages under

LPS-induced lethality and pathological changes of lung

Lung tissue pathological changes were detected by H&E staining. As shown in Fig. 1, the lung architecture of ARDS group showed distinct changes starting at 6 h after LPS induction (LPS6h) when compared to controls. This was accompanied with significant infiltration of inflammatory cells, extensive thickening of the alveolar wall and demolished structure of pulmonary alveoli in the ARDS group. However, after 4 days of LPS induction (LPS4d), the alveolar destruction of ARDS group was ameliorated

Discussion

The resolution of inflammation has been an under-represented focus of inflammation research. It is now clear that the resolution phase of an inflammatory response is an active and orchestrated rather than a passive process, similar in complexity to the onset and maintenance of inflammation [10]. Resolvins are generated within the resolution phase of ongoing inflammation and governs the onset, evolution and outcomes of inflammation and actively stimulate the restoration of tissue homeostasis [9]

Conclusion

In summary, we demonstrated that the endogenous RvD1 underwent a decrease in expression followed by a gradual increase that basically coincide with the lung injury recovery in a rat model of self-resolution LPS-induced ARDS and inflammation. Our findings have provided clues that endogenous RvD1 may play an important role in facilitating disease recovery during ARDS although a definite role of RvD1 in this pathology merits further studies. Our results may help define the optimal therapeutic

Author contribution

Conceived and designed the experiments: QW, TW, YL. Performed the experiments: WS, ZW, PG, XZ, QD, WX, CM, LW. Analyzed the data: WS, ZW, QW, TW, YL. Contributed to discussion and wrote the paper: WS, ZW, ZX, WX, QW, TW, YL.

Acknowledgment

This study was supported by a grant from National Natural Science Foundation of China (No. 81370112, 81070060 and 30930089) and Key Clinical Project of Ministry of Health of China (2010-47).

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    Wei Sun and Zaiping Wang contributed equally to this work.

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