Elsevier

Biomedicine & Pharmacotherapy

Volume 92, August 2017, Pages 519-527
Biomedicine & Pharmacotherapy

Lutein mitigates cyclophosphamide induced lung and liver injury via NF-κB/MAPK dependent mechanism

https://doi.org/10.1016/j.biopha.2017.05.103Get rights and content

Abstract

This study targeted to test the potential protective role of lutein against lung and liver damage associated with cyclophosphamide (CP) administration. Lutein was given orally for 5 days at two different doses both before and after CP injection. Results have shown that CP administration caused marked pulmonary and hepatic injurious effects in mice. Lung damage was evident through increased lung wet/dry ratio, elevated inflammatory cells infiltration into the pulmonary tissues, increased total protein content and lactate dehydrogenase (LDH) activity in the broncho-alveolar lavage fluid. Estimation of high levels of serum transaminases, alkaline phosphatase and LDH in serum revealed hepatic injury. Histopathological examination of both organs confirmed the biochemical analysis. Elevation of oxidative stress along with depressed anti-oxidant status of lung and liver were evident in CP-intoxicated animals. Furthermore, CP induced elevation of inflammatory cytokines (NOx, TNF-α, IL-6) contaminant with activation of nuclear factor kappa-B (NF-κB) and p38 mitogen activated protein kinase (p38-MAPK). On the other side, lutein treatment successfully protected the lung and the liver as indicated by improvement of the biochemical and histopathological parameters. These results suggest that lutein can ameliorate CP-induced pulmonary and hepatic oxidative injurious effects via inhibition of reactive oxygen species (ROS)/NF-κB/MAPK pathway.

Introduction

Cyclophosphamide (CP) is an oxazaphosphorine alkylating agent used for neoplastic diseases and as an immunosuppressive agent in organ transplantation although its use has been associated with multiple fatal organ toxicity [1]. CP can induce different pathological patterns of lung injury. Upon administration, CP enhances lung toxicity which may develop into lung fibrosis [2]. Additionally, CP possesses potent hepatotoxic adverse effects which include oxidative, inflammatory and fibrotic reactions. The cytotoxic effects of CP results mainly from its toxic metabolite, acrolein, which alkylates DNA and other cellular structures producing cross-links [3], [4]. Oxidative stress has a great role in mediating CP-induced pulmonary and hepatic toxicities. Previous studies have documented the remarkable suppression of the antioxidant defense system after CP exposure in the lung and liver tissues. Furthermore, reactive oxygen species (ROS) overproduction activates massive inflammatory cell infiltration like neutrophils, monocytes and macrophages, into the pulmonary tissues leading to pulmonary fibrosis [5], [6]. The absence of two key detoxifying enzymes (aldehyde oxidase and aldehyde dehydrogenase) in the lung tissue is considered as one of the main causes of selective CP-induced pulmonary toxicity [5], [7]. Generation of ROS induces the activation of multiple signaling molecules as nuclear factor kappa-B (NF-κB) which modulates different steps in the inflammatory cascade [8], [9]. In this regard, it is acceptable to presume that agents having the ability to decrease oxidative stress and ROS generation can counteract CP-induced oxidative and inflammatory damage. Mitogen activated protein kinases (MAPKs) are important regulatory proteins which include c-jun N-terminal kinase (JNK), extracellular signal regulated kinase (ERK) and p38 subfamilies. These proteins are linked to extracellular signals transduction into intracellular responses. MAPKs can control inflammatory and immune responses and expression of multiple cytokines [10]. Recent studies have demonstrated that these proteins are implicated in mediating CP-induced toxicity [11], [12].

Lutein is a natural occurring xanthophyll carotenoid. As all carotenoids, humans cannot synthesize lutein and so its presence in human blood and tissues comes from the ingestion of food or supplement sources [13]. Lutein is consumed through fruits and vegetables like egg yolk, corn, broccoli, spinach, kiwi, zucchini, peas and kale [14]. Lutein has shown protective activities against many inflammatory disorders such as diabetic retinopathy, ocular diseases [15], [16], kidney damage [17] and pulmonary lesions [18]. The molecular mechanisms underlying the cytoprotective role of lutein have been attributed to its potent antioxidant activity as well as immuno-modulatory effects. The antioxidant activity of lutein depends on its chemical structure as it has conjugated double bonds as well as hydroxyl groups at both ends. Furthermore, lutein modulates the production of inflammatory cytokines as nitric oxide (NO) and tumor necrosis factor-alpha (TNF-α) in aqueous humor and lung tissues. Lutein decreases the expression of inducible nitric oxide synthetase (iNOS) and cyclo-oxygenase-2 (COX-2) in RAW cells (rat alveolar macrophages) [18], [19], [20]. Recent studies have demonstrated the role of lutein in the inhibition of NF-κB pathway [21], [22]. Until now, nothing has been discovered regarding the effect of lutein against CP-induced pulmonary and hepatic damage. Therefore, the objectives of the present study were to investigate the effect of lutein against CP-induced lung and liver damage and to provide a better understanding of the possible mechanisms by evaluating different parameters of toxicity, inflammatory and apoptotic pathways.

Section snippets

Animals

Adult male Swiss albino mice (25–27 g) were allowed access to tap water and standard laboratory food throughout the acclimatization and experimental periods. The study protocol was conducted according to the ethical principles and guidelines of the use, care, and handling of experimental animals adopted by “Research Ethics Committee of Taibah University” (Saudi Arabia) which are in accordance with the Principles of Laboratory Animal Care (NIH 1985).

Drugs and chemicals

Lutein was purchased as capsules (US Nutrition

Effects on the lung W/D ratio and protein content

CP administration resulted in a significant increase in the lung W/D ratio as well as total protein content compared to control animals (Fig. 1A and B). Furthermore, LDH was significantly higher in CP group (Fig. 1C). Lutein treatment significantly lowered these parameters compared to CP group.

Effects on lung inflammation

After single injection of CP, the total and differential numbers of inflammatory cells in BALF were significantly elevated compared to the control group (Table 1). However, lutein administration at 40 and

Discussion

Despite wide spectrum of clinical uses for CP, it exerts severe cytotoxic effect on the healthy tissues in humans and experimental animals [11]. The cytotoxicity of CP is associated with generation of acrolein during drug metabolism which results in overproduction of ROS, lipid peroxidation, depression in the antioxidant defense system and severe inflammatory reaction due to the recruitment of neutrophils [2], [29]. Recently, more attention has been paid to the role of the dietary antioxidants

Conflict of interest statement

The authors declare no conflict of interest.

Acknowledgement

The authors acknowledge the Deanship of Scientific Research (DSR), Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia, for providing assistance.

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