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Krill oil and low-dose aspirin combination mitigates experimentally induced silicosis in rats: role of NF-κB/TGF-β1/MMP-9 pathway

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Abstract

This study is an attempt to assess pulmonary protective and antifibrotic potentials of a combination of aspirin, a widely used anti-inflammatory and cardioprotective agent, and krill oil, a naturally occurring omega-3 fatty acid source, against silica-induced pulmonary injury. For silicosis induction, silica particles (50 mg/rat, 0.1 mL 0.9% NaCl) were instilled intranasally into rats. Aspirin (10 mg/kg/day), krill oil (40 mg/kg/day), or their combination was administered orally for 56 days following silica exposure. Results showed that oral aspirin and krill oil combination significantly mitigated silica-induced pulmonary injury. Bronchoalveolar lavage fluid examination showed a decreased lactate dehydrogenase activity, total protein content, and accumulation of total and differential inflammatory cells. Oral aspirin and krill oil combination significantly attenuated silica-induced oxidative stress through the restoration of reduced glutathione concentration and catalase activity in addition to alleviation of elevated malondialdehyde and total nitric oxide contents. Moreover, aspirin and krill oil combination revealed considerable mitigation of silica-induced upregulated expression of the inflammatory and fibrotic mediators: nuclear factor kappa-B, transforming growth factor-β1, and matrix metalloproteinase-9. The antifibrotic effect was also evidenced through the decreased hydroxyproline content and the obvious restoration of lung architecture, as demonstrated upon histopathological examination. In conclusion, oral aspirin and krill oil combination can confer pulmonary protective, anti-inflammatory, and antifibrotic potentials against silica-induced pulmonary injury. This impact could be credited to the ability of this combination to activate resolution mechanisms, which, in turn, suppress the expression of inflammatory and fibrotic biomarkers and replenish antioxidant stores.

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All data analyzed or generated during this study are included in this article and its supplementary information files.

References

  • Abdelaziz RR, Elkashef WF, Said E (2016) Tadalafil reduces airway hyperactivity and protects against lung and respiratory airways dysfunction in a rat model of silicosis. Int Immunopharmacol. 40:530–541

    Article  CAS  Google Scholar 

  • Araujo P, Zhu H, Breivik JF, Hjelle JI, Zeng Y (2014) Determination and structural elucidation of triacylglycerols in krill oil by chromatographic techniques. Lipids. 49(2):163–172

    Article  CAS  Google Scholar 

  • Ashcroft T, Simpson JM, Timbrell V (1988) Simple method of estimating severity of pulmonary fibrosis on a numerical scale. Journal of Clinical Pathology. 41(4):467–470

    Article  CAS  Google Scholar 

  • Basil MC, Levy BD (2016) Specialized pro-resolving mediators: endogenous regulators of infection and inflammation. Nature Reviews Immunology. 16(1):51–67

    Article  CAS  Google Scholar 

  • Bergman I, Loxley R (1963) Two improved and simplified methods for the spectrophotometric determination of hydroxyproline. Analytical Chemistry. 35(12):1961–1965

    Article  CAS  Google Scholar 

  • Burri L, Hoem N, Banni S, Berge K (2012) Marine omega-3 phospholipids: metabolism and biological activities. International journal of molecular sciences. 13(11):15401–15419

    Article  CAS  Google Scholar 

  • Chakrabarti S, Patel KD (2005) Matrix metalloproteinase-2 (mmp-2) and mmp-9 in pulmonary pathology. Experimental lung research. 31(6):599–621

    Article  CAS  Google Scholar 

  • Chakraborti S, Sarkar J, Pramanik PK, Chakraborti T (2017) Role of proteases in lung disease: a brief overview. Proteases in Human Diseases:333–374

  • Chiurchiù V, Leuti A, Maccarrone M (2018) Bioactive lipids and chronic inflammation: managing the fire within. Frontiers in immunology. 9:38

    Article  Google Scholar 

  • de Oliveira HDA, de Melo EBB, Silva JD et al (2017) Therapeutic effects of bone marrow-derived mononuclear cells from healthy or silicotic donors on recipient silicosis mice. Stem cell research & therapy. 8(1):259

    Article  Google Scholar 

  • Ding M, Chen F, Shi X, Yucesoy B, Mossman B, Vallyathan V (2002) Diseases caused by silica: mechanisms of injury and disease development. International Immunopharmacology. 2(2):173–182

    Article  CAS  Google Scholar 

  • Fattori V, Zaninelli TH, Rasquel-Oliveira FS, Casagrande R, Verri WA Jr (2020) Specialized pro-resolving lipid mediators: a new class of non-immunosuppressive and non-opioid analgesic drugs. Pharmacological research. 151:104549

    Article  CAS  Google Scholar 

  • Ferramosca A, Conte A, Zara V (2015) Krill oil ameliorates mitochondrial dysfunctions in rats treated with high-fat diet. BioMed Research International. 2015:645984

    Article  Google Scholar 

  • Gil-Villa AM, Alvarez AM, Velásquez-Berrío M, Rojas-López M, Cadavid J, A. P. (2020) Role of aspirin-triggered lipoxin a4, aspirin, and salicylic acid in the modulation of the oxidative and inflammatory responses induced by plasma from women with pre-eclampsia. American Journal of Reproductive Immunology. 83(2):e13207

    Article  Google Scholar 

  • Helal MG, El-Kashef DH (2020) Krill oil alleviates oxidative stress, iron accumulation and fibrosis in the liver and spleen of iron-overload rats. Environmental Science and Pollution Research. 27(4):3950–3961

    Article  CAS  Google Scholar 

  • Helal MG, Said E (2019) Carvedilol attenuates experimentally induced silicosis in rats via modulation of p-akt/mtor/tgfβ1 signaling. Int Immunopharmacol. 70:47–55

    Article  CAS  Google Scholar 

  • Helal MG, Megahed NA, Abd Elhameed AG (2019) Saxagliptin mitigates airway inflammation in a mouse model of acute asthma via modulation of nf-kb and tlr4. Life sciences. 239:117017

    Article  CAS  Google Scholar 

  • Hemmati AA, Nazari Z, Samei M (2008) A comparative study of grape seed extract and vitamin e effects on silica-induced pulmonary fibrosis in rats. Pulmonary pharmacology & therapeutics. 21(4):668–674

    Article  CAS  Google Scholar 

  • Hu X, Shen H, Wang Y, Zhang L, Zhao M (2019) Aspirin-triggered resolvin d1 alleviates paraquat-induced acute lung injury in mice. Life sciences. 218:38–46

    Article  CAS  Google Scholar 

  • Ierna M, Kerr A, Scales H, Berge K, Griinari M (2010) Supplementation of diet with krill oil protects against experimental rheumatoid arthritis. BMC Musculoskelet Disord. 11:136–136

    Article  Google Scholar 

  • Jagirdar J, Begin R, Dufresne A, Goswami S, Lee TC, Rom WN (1996) Transforming growth factor-beta (tgf-beta) in silicosis. American journal of respiratory and critical care medicine. 154(4 Pt 1):1076–1081

    Article  CAS  Google Scholar 

  • Kajikawa S, Imada K, Takeuchi T, Shimizu Y, Kawashima A, Harada T, Mizuguchi K (2011) Eicosapentaenoic acid attenuates progression of hepatic fibrosis with inhibition of reactive oxygen species production in rats fed methionine-and choline-deficient diet. Digestive diseases and sciences. 56(4):1065–1074

    Article  CAS  Google Scholar 

  • Kumar Bhatt L, Addepalli V (2011) Minocycline with aspirin: an approach to attenuate diabetic nephropathy in rats. Renal failure. 33(1):72–78

    Article  Google Scholar 

  • Leung CC, Yu IT, Chen W (2012) Silicosis. Lancet (London, England). 379(9830):2008–2018

    Article  CAS  Google Scholar 

  • Leuti A, Maccarrone M, Chiurchiù V (2019) Proresolving lipid mediators: endogenous modulators of oxidative stress. Oxidative medicine and cellular longevity. 2019

  • Li J-p, Guo J-m, Hua Y-q et al (2016) The mixture of salvia miltiorrhiza–carthamus tinctorius (danhong injection) alleviates low-dose aspirin induced gastric mucosal damage in rats. Phytomedicine. 23(6):662–671

    Article  Google Scholar 

  • Liu Y, Nong L, Jia Y, Tan A, Duan L, Lu Y, Zhao J (2020) Aspirin alleviates hepatic fibrosis by suppressing hepatic stellate cells activation via the tlr4/nf-κb pathway. Aging (Albany NY). 12(7):6058–6066

    Article  CAS  Google Scholar 

  • Lobraico JM, DiLello LC, Butler AD, Cordisco ME, Petrini JR, Ahmadi R (2015) Effects of krill oil on endothelial function and other cardiovascular risk factors in participants with type 2 diabetes, a randomized controlled trial. BMJ open diabetes research & care. 3(1):e000107

    Article  Google Scholar 

  • Lopes-Pacheco M, Bandeira E, Morales MM (2016) Cell-based therapy for silicosis. Stem Cells Int. 2016:5091838–5091838

    Article  Google Scholar 

  • López-Cervantes J, Sánchez-Machado DI, Gutiérrez-Coronado MA, Ríos-Vázquez NJ (2006) Quantification of astaxanthin in shrimp waste hydrolysate by hplc. Biomed Chromatogr. 20(10):981–984

    Article  Google Scholar 

  • Lu C, Sun T, Li Y, Zhang D, Zhou J, Su X (2017) Modulation of the gut microbiota by krill oil in mice fed a high-sugar high-fat diet. Frontiers in Microbiology. 8(905)

  • Maki, K. C., Reeves, M. S., Farmer, M., et al. (2009). Krill oil supplementation increases plasma concentrations of eicosapentaenoic and docosahexaenoic acids in overweight and obese men and women. Nutrition research (New York, N.Y.). 29(9), 609-615.

  • Martins V, Valença SS, Farias-Filho FA, Molinaro R, Simões RL, Ferreira TPT, e Silva PMR, Hogaboam CM, Kunkel SL, Fierro IM, Canetti C, Benjamim CF (2009) Atla, an aspirin-triggered lipoxin a4 synthetic analog, prevents the inflammatory and fibrotic effects of bleomycin-induced pulmonary fibrosis. The Journal of Immunology. 182(9):5374–5381

    Article  CAS  Google Scholar 

  • Mishra A, Chaudhary A, Sethi S (2004) Oxidized omega-3 fatty acids inhibit nf-κb activation via a pparα-dependent pathway. Arteriosclerosis, Thrombosis, and Vascular Biology. 24(9):1621–1627

    Article  CAS  Google Scholar 

  • Mossman BT, Glenn RE (2013) Bioreactivity of the crystalline silica polymorphs, quartz and cristobalite, and implications for occupational exposure limits (oels). Critical reviews in toxicology. 43(8):632–660

    Article  CAS  Google Scholar 

  • Ooi GC, Tsang KW, Cheung TF et al (2003) Silicosis in 76 men: qualitative and quantitative ct evaluation--clinical-radiologic correlation study. Radiology. 228(3):816–825

    Article  Google Scholar 

  • Pollard KM (2016) Silica, silicosis, and autoimmunity. Frontiers in Immunology. 7(97)

  • Ramírez G, Hagood JS, Sanders Y, Ramírez R, Becerril C, Segura L, Barrera L, Selman M, Pardo A (2011) Absence of thy-1 results in tgf-β induced mmp-9 expression and confers a profibrotic phenotype to human lung fibroblasts. Laboratory Investigation. 91(8):1206–1218

    Article  Google Scholar 

  • Reynolds, K., Jerome, J. (2020). Silicosis. Workplace Health & Safety. 0(0), 2165079920967923.

  • Sellamuthu R, Umbright C, Roberts JR, Young SH, Richardson D, McKinney W, Chen BT, Li S, Kashon M, Joseph P (2017) Molecular mechanisms of pulmonary response progression in crystalline silica exposed rats. Inhalation toxicology. 29(2):53–64

    Article  CAS  Google Scholar 

  • Serhan CN (2005) Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution. Prostaglandins, leukotrienes and essential fatty acids. 73(3-4):141–162

    Article  CAS  Google Scholar 

  • Spite M, Norling LV, Summers L, Yang R, Cooper D, Petasis NA, Flower RJ, Perretti M, Serhan CN (2009) Resolvin d2 is a potent regulator of leukocytes and controls microbial sepsis. Nature. 461(7268):1287–1291

    Article  CAS  Google Scholar 

  • Stockert, K. (2020). Lipidmediatoren und ihre rolle bei entzündungen und allergien. In: (ed)^(eds). Allergieprävention: Moderne strategien der allergieforschung im dialog mit der tcm, edn. Berlin, Heidelberg: Springer Berlin Heidelberg. p^pp 185-245.

  • Ursoniu S, Sahebkar A, Serban MC, Antal D, Mikhailidis DP, Cicero A, Athyros V, Rizzo M, Rysz J, Banach M, Lipid and Blood Pressure Meta-analysis Collaboration Group (2017) Lipid-modifying effects of krill oil in humans: systematic review and meta-analysis of randomized controlled trials. Nutrition reviews. 75(5):361–373

    Article  Google Scholar 

  • Van den Steen PE, Dubois B, Nelissen I, Rudd PM, Dwek RA, Opdenakker G (2002) Biochemistry and molecular biology of gelatinase b or matrix metalloproteinase-9 (mmp-9). Critical reviews in biochemistry and molecular biology. 37(6):375–536

    Article  Google Scholar 

  • Wang X, Lu J, Khaidakov M, Mitra S, Ding Z, Raina S, Goyal T, Mehta JL (2012) Aspirin suppresses cardiac fibroblast proliferation and collagen formation through downregulation of angiotensin type 1 receptor transcription. Toxicology and Applied Pharmacology. 259(3):346–354

    Article  CAS  Google Scholar 

  • Zhang Z, Li S, Deng J, Yang S, **ang Z, Guo H, ** H, Sang M, Zhang W (2020) Aspirin inhibits endometrial fibrosis by suppressing the tgf-β1-smad2/smad3 pathway in intrauterine adhesions. International Journal of Molecular Medicine. 45(5):1351–1360

    CAS  Google Scholar 

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Acknowledgments

The author expresses gratitude to Dr. Walid Abdo, “Associate Professor of Veterinary Pathology, Faculty of Veterinary Medicine, Kufr-Elsheikh University, Egypt” for his cooperation in the histopathological and immunohistochemical assessment, and to Dr. Sara Gohar, “Assistant Lecturer of scientific writing, English Department, Horus University-Egypt” for her thorough revision of the manuscript for the typo, grammar, and punctuation errors.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt

    Ahmed G. Abd Elhameed

  2. Department of Pharmacology, Faculty of Pharmacy, Horus University-Egypt, New Damietta, Egypt

    Ahmed G. Abd Elhameed

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  1. Ahmed G. Abd Elhameed
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This is a single-author research article where AG.A conceived, designed, and performed the experiments, analyzed the data, and wrote the manuscript.

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Correspondence to Ahmed G. Abd Elhameed.

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Experimental work presented in the current study was done following the animal care and use guidelines and approved by Pharmacology and Toxicology Department, Faculty of Pharmacy, Mansoura University, which is in agreement with the Laboratory Animal Care guidelines (NIH publication no. 85–23, revised in 1985).

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Responsible Editor: Mohamed M. Abdel-Daim

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Highlights

• Aspirin and krill oil combination exhibited antioxidant, anti-inflammatory, and antifibrotic actions.

• Aspirin and krill oil combination protect against silicosis-induced pulmonary fibrosis.

• The pulmonary protective and antifibrotic effects of aspirin and krill oil combination may be induced via the stimulation of aspirin triggered specialized proresolving lipid mediator (AT-SPM) biosynthesis and inhibition NF-κB, TGF-β1, and MMP-9 expression in the lung.

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Abd Elhameed, A.G. Krill oil and low-dose aspirin combination mitigates experimentally induced silicosis in rats: role of NF-κB/TGF-β1/MMP-9 pathway. Environ Sci Pollut Res 28, 19272–19284 (2021). https://doi.org/10.1007/s11356-020-11921-7

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  • DOI: https://doi.org/10.1007/s11356-020-11921-7

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