Cyclophosphamide-induced Lung Toxicity Research Articles

Omarigliptin/rosinidin combination ameliorates cyclophosphamide-induced lung toxicity in rats: The interaction between glucagon-like peptide-1, TXNIP/NLRP3 inflammasome signaling, and PI3K/Akt/FoxO1 axis

Cyclophosphamide is an anti-neoplastic drug that has shown competence in the management of a broad range of malignant tumors. In addition, it represents a keystone agent for management of immunological conditions. Despite these unique properties, induction of lung toxicity may limit its clinical use. Omarigliptin is one of the dipeptidyl peptidase-4 inhibitors that has proven efficacy in management of diabetes mellitus. Rosinidin is an anthocyanidin flavonoid that exhibited promising results in management of diseases characterized by oxidative stress, inflammation, and apoptosis. The present work investigated the possible effects of omarigliptin with or without rosinidin on cyclophosphamide-induced lung toxicity with an exploration of the molecular mechanisms that contribute to these effects. In a rodent model of cyclophosphamide elicited lung toxicity, the potential efficacy of omarigliptin with or without rosinidin was investigated at both the biochemical and the histopathological levels. Both omarigliptin and rosinidin exhibited a synergistic ability to augment the tissue antioxidant defenses, mitigate the inflammatory pathways, restore glucagon-like peptide-1 levels, modulate high mobility group box 1 (HMGB1)/receptors of advanced glycation end products (RAGE)/nuclear factor kappa B (NF-κB) axis, downregulate the fibrogenic mediators, and create a balance between the pathways involved in apoptosis and the autophagy signals in the pulmonary tissues. In conclusion, omarigliptin/rosinidin combination may be introduced as a novel therapeutic modality that attenuates the different forms of lung toxicities induced by cyclophosphamide.

Protective effect of alogliptin against cyclophosphamide-induced lung toxicity in rats: Impact on PI3K/Akt/FoxO1 pathway and downstream inflammatory cascades

Cyclophosphamide (CP)-induced lung toxicity is a remaining obstacle against the beneficial use of this chemotherapeutic agent. More considerations were given to the role of Alogliptin (ALO) in ameliorating CP-induced toxicities in many tissues. We designed this study to clarify the protective potential of ALO against CP-induced lung toxicity in rats. ALO was administered for 7 days. Single-dose CP was injected on the 2nd day (200 mg/kg: i.p.) to induce lung toxicity. Rats were divided into four groups: control, ALO-treated, CP-treated and ALO + CP-treated group. Leucocytic count, total proteins, LDH activity, TNF-α, and IL-6 were estimated in the bronchoalveolar lavage fluid (BALF). The oxidative/antioxidants (MDA, Nrf2, TAO and GSH), inflammatory (NFκB), fibrotic (TGF-β1) and apoptotic (PI3K/Akt/FoxO1) markers in pulmonary homogenates were biochemically evaluated. Rat lung sections were examined histologically (light and electron microscopic examination) and immunohistochemically (for iNOS and CD68 positive alveolar macrophages). CP significantly increased oxidative stress, inflammation, fibrosis, and apoptosis markers as well as deteriorated the histopathological pulmonary architecture. These hazardous effects were significantly ameliorated by ALO treatment. ALO protected against CP-induced lung toxicity by mitigating the oxidative, inflammatory and fibrotic impacts making it a promising pharmacological therapy for mitigating CP-induced lung toxicity.Graphical abstract

Antiproliferative, Apoptotic Effects and Suppression of Oxidative Stress of Quercetin against Induced Toxicity in Lung Cancer Cells of Rats: In vitro and In vivo Study

In the present study, quercetin was examined against lung human cancer cells using A549 and H69 cancer cell lines in addition to normal non cancer cells (W138). Two genes Bax and Bcl-2 that play an important role in apoptosis pathways were investigated. Also Immunohistochemical study for caspase-3 which is considered as indicator for apoptosis was performed. Quercetin showed good anti proliferative activity against tested lung cancer cell lines, IC50 values on A549 are 8.65, 7.96 and 5.14 µg/ml at 24, 48 and 72h respectively. Also significant effects of quercetin on Bax, Bcl-2 and caspase-3 were observed, that can prove its ability to induce apoptosis. On the other hand quercetin showed good therapeutic effects against cyclophosphamide induced lung toxicity that were observed in the histopathology study. In vitro studies were also performed such as cell cycle analysis through flowcytometry. The obtained results from all these performed analysis proved that quercetin can induce apoptosis in human lung cancer cells, additionally quercetin showed ability to reduce MDA and increase SOD and GSHP levels which indicates its ability in suppressing oxidative stress, Quercetin has played a therapeutic role in cyclophosphamide induced lung toxicity as it has improved restoring of the damaged lung tissue as discussed in this research work.

The Protective Effect of Propolis Compared to Vitamins C and E Antioxidant Mixture in Cyclophosphamide-Induced Lung Toxicity In Mice

The Protective Effect of Propolis Compared to Vitamins C and E Antioxidant Mixture in Cyclophosphamide-Induced Lung Toxicity In Mice

The potential protective role of coenzyme q10 on the cyclophosphamide-induced lung toxicity in adult male albino rats: a histological and ultrastructural study

<p class="abstract"><strong>Background:</strong> Cyclophosphamide is anticancer and immunosuppressant agent used to treat malignant and autoimmune diseases. Its long-term use causes side effects, as infertility and pulmonary toxicity. Coenzyme Q10; the only synthesized antioxidant in human body, acts as powerful antioxidant, scavenging free radicals, and inhibiting lipid peroxidation. Aim of present study was to examine effect of coenzyme Q10 on blood biochemical profiles, histopathological changes in lungs of adult rats exposed to cyclophosphamide-induced toxicity.</p><p class="abstract"><strong>Methods:</strong> 36 adult male albino rats divided into four groups; control and three experimental each having 9 rats. First experimental group received coenzyme Q10, second received cyclophosphamide while third group received coenzyme Q10 along with cyclophosphamide. Experiment lasted for 7 days. On 8th day, animals were sacrificed by decapitation. Lung tissue samples were collected for histopathological examination. SOD (superoxide dismutase) and MDA (malondialdehyde) levels were determined and used for statistical analysis. </p><p class="abstract"><strong>Results:</strong> In coenzyme Q10 treated group, H&E stained sections revealed normal respiratory alveoli. Ultrathin sections revealed normal alveolar septa, pneumocyte and blood capillaries contain erythrocytes. In cyclophosphamide treated group, H&E stained sections revealed peribronchial and interstitial fibrosis. Ultrathin sections revealed alveoli having apparent free lumen with extravasated erythrocytes. Alveolar septa revealed collagen fibrils deposits, and proliferated fibroblasts. In combined coenzyme Q10 and cyclophosphamide treated group, H&E stained sections revealed marked decrease of inter-alveolar tissue thickening. Ultrathin sections revealed destructed alveolar septa with dissociated remnants of collagen fibrils. Blood capillaries appeared wide, containing monocytes and erythrocytes.</p><p class="abstract"><strong>Conclusions:</strong> Administration of coenzyme Q10 with cyclophosphamide is advised to alleviate cyclophosphamide-induced lung toxicity.</p>

Role of venlafaxine in prevention of cyclophosphamide-induced lung toxicity and airway hyperactivity in rats

Cyclophosphamide (CP) is a drug used in chemotherapy and management of neoplastic diseases. This study aimed to investigate the prophylactic impacts of venlafaxine against CP-induced lung toxicity in rats. Rats were assigned randomly into 3 groups; control, CP (150 mg/kg) and CP/venlafaxine (50 mg/kg). On the end day, rats were sacrificed then bronchoalveolar fluid (BALF) and lungs were harvested. CP produced significant decrease in animal body weights and significant increase in lung/body weight ratio; levels of LDH, total protein, total and differential cell counts in BALF in comparison with control group. Moreover, significant elevation incontents of MDA, NOx, TNF-α and IL-1β and significant decline in GSH, SOD activities were observed in lung tissues. CP increased the response of tracheal zigzag to ACh. Histopathological results showed that CP increased inflammation and fibrosis in lung tissues. Venlafaxine restored most parameters to the normal levels. This protective effect of venlafaxine could be linked to its ability to reduce oxidative stress and inflammation.

The protective effect of quercetin on cyclophosphamide-Induced lung toxicity in rats

Cyclophosphamide (CYP) is an anticancer agent widely used in chemotherapy. It has been suggested that CYP causes toxicity in many organs, including the lungs and testes. Many studies have indicated that some antioxidants have possible protective effects against CYP’s side effects. This study aimed to investigate the protective effect of quercetin (QUE) on CYP-induced lung toxicity in rats using histologic and biochemical methods.In the study, 50 male Sprague-Dawley rats weighing 220–250g were used. There were 4 experimental groups and 1 control group. Group I is the control group, which was given only intragastric (i.g.) solvent (corn oil) for 7days. Group II was given i.g. corn oil for 7days as a placebo, and a single dose of intraperitoneal (i.p.) CYP (200mg/kg) was given on day 7. Groups III and IV, respectively, were given QUE in doses of 50 and 100mg/kg, dissolved in corn oil, and administered i.g. for 7days. In addition, a single dose of CYP (200mg/kg, i.p.) was administered on the 7th day of study. In Group V, a 100mg/kg dose of QUE was given to rats i.g. for 7days. On the 8th day of the experiment, all groups of rats’ blood and lung tissue samples were collected for analysis of oxidative stress parameters and histopathological examinations.In the biochemical result (although oxidative parameters were increased in favor of tissue damage) QUE administration revealed attenuated CYP toxicity in the rats ‘lungs. In histologic analysis, QUE prevented the CYP-mediated tissue damage and the increase in mast-cell densities in the rats’ lung tissues.The results of the present study have revealed that QUE provides a possible protective effect by inhibiting ROS and mast cell degranulation in induced lung damage.

Blueberry anthocyanins-enriched extracts attenuate the cyclophosphamide-induced lung toxicity

The influence of blueberry anthocyanins-enriched extracts (BAE) on cyclophosphamide (CTX)-induced lung damage was investigated. BAE (20 and 80mg/kg/d) were orally dosed to rats 7d both before and after CTX administration (100mg/kg, intraperitoneal injection, single dose). The results showed CTX treatment induced obvious pathological pulmonary injury with raised injury score and lung/body weight ratio. In CTX group, the activity of lysosomal proteases, lung permeability and the number of neutrophil infiltrates all elevated. On the other hand, claudin-4 and zonula occluden-1 protein levels decreased. And also changes of oxidative stress and inflammatory cytokines parameters together with nuclear factor-κB activation were shown. Improvement of all above-mentioned physiological and biochemical parameters was exhibited in BAE groups, with a dose-dependent manner. In conclusion, BAE attenuate the CTX-induced lung toxicity, antioxidant and anti-inflammatory characteristics are involved in the protective mechanism of BAE.

When GLP-1 hits the liver: a novel approach for insulin resistance and NASH

nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum ranging from simple steatosis to steatohepatitis (NASH), increasing fibrosis and eventually, cirrhosis ([22][1]). Importantly, NASH accompanied by fibrosis and severe inflammation is the most relevant predictor for disease progression

Biochemical indices of cyclophosphamide-induced lung toxicity

Cyclophosphamide (CP) requires metabolic activation for its therapeutic action, and this metabolism results in the formation of two toxic metabolites, acrolein (ACR) and phosphoramide mustard (PM). To determine which metabolite is responsible for CP-induced lung injury, biochemical indices of toxicity and histopathologic changes in the lungs of CP-, ACR-, or PM-treated rats were evaluated. Experimental rats were given 200 mg kg −1 day −1 CP, 5 mg kg −1 day −1 ACR, or 50 mg kg −1 day −1 PM for 1 to 3 days, or were given 100 mg/kg CP for 1 day; control rats received vehicle alone for 1 to 3 days. Twenty-four hr after the last treatment the lungs were analyzed for (a) microsomal NADPH cytochrome c reductase and aniline hydroxylase activities; (b) microsomal lipid peroxide formation; and (c) glutathione content. In rats given 200 mg/kg CP, NADPH cytochrome c reductase and aniline hydroxylase activities decreased 66% ( p < 0.001) and 40% ( p < 0.001), respectively. Lipid peroxidation was increased 100 to 200% ( p < 0.001), and glutathione content was increased 60 to 70% ( p < 0.001). Similar but smaller changes were observed in the lungs of rats given 100 mg/kg CP. In rats given ACR, NADPH cytochrome c reductase and aniline hydroxylase activities decreased 6% ( p < 0.001) and 45% ( p < 0.001), and glutathione content increased 38% ( p < 0.05). In rats given PM, none of the biochemical variables examined were significantly altered. Phenobarbital and SKF 525-A prevented CP-induced biochemical alterations. Despite CP-induced biochemical alterations, no significant light microscopic changes were observed in the lungs. Alterations in lung mixed-function oxidase activity, GSH content, and microsomal lipid peroxide formation are early biochemical indices of CP-induced lung toxicity, and are due at least in part to the reactive metabolite ACR.