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