Pulmonary, gastrointestinal and urogenital pharmacologyCostunolide and Dehydrocostuslactone, two natural sesquiterpene lactones, ameliorate the inflammatory process associated to experimental pleurisy in mice
Introduction
Injection of carrageenan (CAR) into the pleural space leads to local inflammation, infiltration by polymorphonuclear leukocytes (PMNs) and lung injury (Cuzzocrea et al., 1999c). This experimental model of pleurisy has been widely used to investigate the pathophysiology of acute inflammation and also to evaluate the efficacy of drugs in inflammation (Nantel et al., 1999). During the inflammatory response, the high production of reactive oxygen and nitrogen species modulate gene expression as well as apoptosis contributing to the amplification of the inflammatory tissue injury (Fialkow et al., 2007). Recently we and others authors have clearly demonstrated that one mechanism through which reactive oxygen species influences the inflammatory response in the experimental model of lung inflammation is through the activation of the redox-sensitive transcription factor NF-κB (Cuzzocrea et al., 2004), that translocates to the nucleus, where it orchestrates the transcription of a number of pro-inflammatory genes (Peters et al., 2000). Consensus-binding sequences for NF-κB have been identified in the promoter regions of several genes implicated in the pathogenesis of acute and chronic inflammation (Baldwin, 2001).
Another hallmarks of the inflammatory response is the activation of the members of transcription factors, Signal Transducers and Activators of transcription family (STATs), which are induced by cytokines at the early phase of the inflammatory process (Pfitzner et al., 2004). The phosphorylated STATs dimers translocate into the nucleus to regulate expression of target genes (Darnell et al., 1994). Among a number of cytokines released during inflammatory response, interferon (IFN)-γ and interleukin (IL-6) play a pivotal role in regulating the expression of inflammatory genes. IFN-γ exclusively transduces its message by activating cytoplasmic STAT1 whereas the pleiotropic cytokine IL-6 predominantly activates STAT3 and to less extent STAT1. Our previous report (Cuzzocrea et al., 1999b) showed a reduction of carrageenan-elicited lung injury in IL-6-KO mice and a significant attenuation of lung inflammation in the IL-6-WT mice treated with anti-IL-6 antibodies. Furthermore, we have demonstrate that the administration of Hypericum perforatum extract as well as natural molecule like glycyrrhizin protected lung tissues in CAR-treated mice in association with reduced STAT3 activation (Menegazzi et al., 2008a). Recently, we have reported that costunolide (CS) and dehydrocostuslactone (DCE) two sesquiterpene lactones present in a number of plants such as Laurus nobilis, strongly and efficiently inhibit IL-6-induced tyrosine phosphorylation of STAT3 in human leukemic cell line THP-1 (Butturini et al., 2011). Furthermore, these compounds exhibit variety of pharmacological activities including anti-inflammatory and anti-bacterial ones (Robles et al., 1995); pro-apoptotic effect in different human cancer cell line (Hung et al., 2010, Park et al., 2001); inhibitory action on NF-κB activation (Koo et al., 2001); Nfr2 expression (Pae et al., 2007) and MAPK activation (Hsu et al., 2009). Moreover, DCE inhibits the constitutive STAT3 activation (Kuo et al., 2009).
Given that CS and DCE have emerged as a potential anti-inflammatory agent, the present study was designed to explore their possible effect in an experimental model of CAR-induced pleurisy as well as to examine the underlying mechanisms responsible for its effects on this model of acute lung injury.
Section snippets
Animals
Male CD mice (weight 20–25 g; Harlan Nossan, Milan, Italy) were used in these studies. The animals were housed in a controlled environment and provided with standard rodent chow and water. Animal care was in compliance with Italian regulations on the protection of animals used for experimental and other scientific purposes (D.M. 116192) as well as with EEC regulations (O.J. of E.C. L358/1 12/18/1986).
Carrageenan-induced pleurisy
Pleurisy by CAR was induced as previously described (Cuzzocrea et al., 2000). Mice were
Effects of CS and DCE on CAR-induced pleurisy
The injection of carrageenan into the pleural cavity of mice elicited an acute inflammatory response characterized by the accumulation of fluid (exudate) that contained large amounts of PMNs. Exudates volume and neutrophil infiltration in lung tissue were attenuated in a dose-dependent fashion by CS and DCE treatments (Fig. 1A and B, respectively).
The dose of 15 mg/kg was used in the following experiments because it was in the logarithmic dose–response curve of inhibition percent (Fig. 1C and D).
Discussion
Experimental study suggests that pleurisy is a useful model for characterizing and/or screening new anti-inflammatory drugs. The early (4 h) and late (48 h) responses of pleurisy are associated with a marked inflammatory reaction in the airways as a result of the release of distinct mediators and activation of different types of immune cells.
The mouse pleurisy model induced by carrageenan is typically associated with an early response to the phlogistic challenge, where several mediators such as
Conclusion
In summary, our studies led to the conclusion that CS and DCE have potential anti-inflammatory actions in the development of CAR-induced pleurisy and support their therapeutic potential for lung inflammatory pathologies.
Acknowledgements
The authors would like to thank Carmelo La Spada and Giovanni Leotta for their excellent technical assistance during this study, Mrs Caterina Cutrona for secretarial assistance and Miss Valentina Malvagni for editorial assistance with the manuscript.
References (34)
- et al.
Mild oxidative stress induces S-glutathionylation of STAT3 and enhances chemosensitivity of tumoural cells to chemotherapeutic drugs
Free Radic. Biol. Med.
(2013) - et al.
Beneficial effects of Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP), a superoxide dismutase mimetic, in carrageenan-induced pleurisy
Free Radic. Biol. Med.
(1999) - et al.
Reactive oxygen and nitrogen species as signaling molecules regulating neutrophil function
Free Radic. Biol. Med.
(2007) - et al.
Oxidative and endoplasmic reticulum stress signaling are involved in dehydrocostuslactone-mediated apoptosis in human non-small cell lung cancer cells
Lung Cancer
(2010) - et al.
Protective effect of Arbutus unedo aqueous extract in carrageenan-induced lung inflammation in mice
Pharmacol. Res.
(2008) - et al.
Glycyrrhizin attenuates the development of carrageenan-induced lung injury in mice
Pharmacol. Res.
(2008) - et al.
Protective effects of St. John׳s wort extract and its component hyperforin against cytokine-induced cytotoxicity in a pancreatic beta-cell line
Int. J. Biochem. Cell Biol.
(2008) - et al.
Myeloperoxidase activity as a quantitative assessment of neutrophil infiltration into ischemic myocardium
J. Pharmacol. Methods
(1985) - et al.
IKKepsilon is part of a novel PMA-inducible IkappaB kinase complex
Mol. Cell.
(2000) - et al.
Parthenolide inhibits activation of signal transducers and activators of transcription (STATs) induced by cytokines of the IL-6 family
Biochem. Biophys. Res. Commun.
(2000)
Poly(ADP-ribosyl)ation in asthma and other lung diseases
Pharmacol. Res.
Series introduction: the transcription factor NF-kappaB and human disease
J. Clin. Invest.
Two naturally occurring terpenes, dehydrocostuslactone and costunolide, decrease intracellular GSH content and inhibit STAT3 activation
PLoS One
Effects of a polyphenol present in olive oil, oleuropein aglycone, in a murine model of intestinal ischemia/reperfusion injury
J. Leukocyte Biol.
Role of interleukin-6 in a non-septic shock model induced by zymosan
Eur. Cytokine Netw.
Inducible nitric oxide synthase-knockout mice exhibit resistance to pleurisy and lung injury caused by carrageenan
Am. J. Respir. Crit. Care Med.
Tempol reduces the activation of nuclear factor-kappaB in acute inflammation
Free Radic. Res.
Cited by (60)
Costunolide alleviated DDC induced ductular reaction and inflammatory response in murine model of cholestatic liver disease
2023, Journal of Traditional and Complementary MedicineDolomiaea costus: an untapped mine of sesquiterpene lactones with wide magnificent biological activities
2023, Natural Product ResearchBotany, traditional uses, phytochemistry and pharmacological properties of Saussurea costus – An endangered plant from Himalaya- A review
2022, Phytochemistry LettersCitation Excerpt :Terpenes are the primary active components, but it encompasses alkaloids, anthraquinones, and flavonoids. S. costus contains various terpenes, like costunolide and dihydrocostunolide, having antiinflammatory and antitumor characteristics (Taniguchi et al., 1995; Chen et al., 1995; Kretschmer et al., 2012; Butturini et al., 2014; Tabata et al., 2015; Peng et al., 2015; Xuejing et al., 2015; Guang et al., 2015; Yang et al., 2016; Kun et al., 2016; Pavan et al., 2016; Peng et al., 2017). 10α-methoxyartemisinic acid (Kun et al., 2016) and costunolide, dehydrocostuslactone along with costic, palmitic, linoleic acids, β-sitosterol, α-cyclocostunolide, β-cyclocostunolide, alantolactone, isoalantolactone and isodihydrocostunolide were also isolated (Robinson et al., 2008; Guang et al., 2015; Lim et al., 2015a).
Aucklandiae Radix and Vladimiriae Radix: A systematic review in ethnopharmacology, phytochemistry and pharmacology
2021, Journal of EthnopharmacologyVariation in essential oil components and anti-inflammatory activity of Allophylus edulis leaves collected in central-western Brazil
2021, Journal of Ethnopharmacology
- 1
Contributed equally.