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HE3286, an oral synthetic steroid, treats lung inflammation in mice without immune suppression.

Conrad D, Wang A, Pieters R, Nicoletti F, Mangano K, van Heeckeren AM, White SK, Frincke JM, Reading CL, Stickney D, Auci DL - J Inflamm (Lond) (2010)

Bottom Line: We tested the ability of this novel synthetic steroid with improved pharmacological properties to limit non-productive lung inflammation in rodents and attempted to gauge its immunological impact.When mice treated for two weeks with HE3286 were challenged with K. pneumoniae, nearly identical survival kinetics were observed in vehicle-treated, HE3286-treated and untreated groups.HE3286 represents a novel, first-in-class anti-inflammatory agent that may translate certain benefits of β-AET observed in rodents into treatments for chronic inflammatory pulmonary disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Harbor Biosciences, 9171 Towne Centre Drive, Suite 180, San Diego, CA 92122, USA. dauci@harborbiosciences.com.

ABSTRACT

Background: 17α-Ethynyl-5-androsten-3β, 7β, 17β-triol (HE3286) is a synthetic derivative of an endogenous steroid androstenetriol (β-AET), a metabolite of the abundant adrenal steroid deyhdroepiandrosterone (DHEA), with broad anti-inflammatory activities. We tested the ability of this novel synthetic steroid with improved pharmacological properties to limit non-productive lung inflammation in rodents and attempted to gauge its immunological impact.

Methods and results: In mice, oral treatment with HE3286 (40 mg/kg) significantly (p < 0.05) decreased neutrophil counts and exudate volumes (~50%) in carrageenan-induced pleurisy, and myeloperoxidase in lipopolysaccharide-induced lung injury. HE3286 (40 mg/kg) was not found to be profoundly immune suppressive in any of the classical animal models of immune function, including those used to evaluate antigen specific immune responses in vivo (ovalbumin immunization). When mice treated for two weeks with HE3286 were challenged with K. pneumoniae, nearly identical survival kinetics were observed in vehicle-treated, HE3286-treated and untreated groups.

Conclusions: HE3286 represents a novel, first-in-class anti-inflammatory agent that may translate certain benefits of β-AET observed in rodents into treatments for chronic inflammatory pulmonary disease.

No MeSH data available.


Related in: MedlinePlus

Effect of HE3286 treatment on MPO levels in LPS induced Lung Injury. On day-1, male C57 black/6 mice were pre-treated (gavage) with HE3286 or 0.1 mL vehicle (HERF405). The next day, mice were challenged with 50 μg of E-coli LPS under direct visualization of trachea under light anesthesia. Sixty minutes after the LPS challenge, mice were treated with a second dose of HE3286, or vehicle. Forty-eight hours after LPS challenge, mice were sacrificed and myeloperoxidase (MPO) activity in lungs determined as previously described [45]. Results are from two identical experiments. Data are expressed as O.D at 460 nM.
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Figure 2: Effect of HE3286 treatment on MPO levels in LPS induced Lung Injury. On day-1, male C57 black/6 mice were pre-treated (gavage) with HE3286 or 0.1 mL vehicle (HERF405). The next day, mice were challenged with 50 μg of E-coli LPS under direct visualization of trachea under light anesthesia. Sixty minutes after the LPS challenge, mice were treated with a second dose of HE3286, or vehicle. Forty-eight hours after LPS challenge, mice were sacrificed and myeloperoxidase (MPO) activity in lungs determined as previously described [45]. Results are from two identical experiments. Data are expressed as O.D at 460 nM.

Mentions: The ability of HE3286 to reduce lung inflammation was also tested in the LPS-induced acute lung injury model. A meta-analysis of two independent studies revealed that when mice pre-treated with HE3286 (40 mg/kg) by oral gavage were challenged with 50 mg of LPS, levels of MPO in lungs at 48 hours were significantly (p < 0.025) reduced (~30%) compared to vehicle-treated animals (Figure 2). Reductions in MPO were also observed with HE3286 at lower doses (12 and 1.2 mg/kg), but as with inflammatory cells and cytokines (TNFa and IL-6) in bronchoalveolar lavage fluid (BAL), upon meta-analysis, these changes did not achieve statistical significance (data not shown).


HE3286, an oral synthetic steroid, treats lung inflammation in mice without immune suppression.

Conrad D, Wang A, Pieters R, Nicoletti F, Mangano K, van Heeckeren AM, White SK, Frincke JM, Reading CL, Stickney D, Auci DL - J Inflamm (Lond) (2010)

Effect of HE3286 treatment on MPO levels in LPS induced Lung Injury. On day-1, male C57 black/6 mice were pre-treated (gavage) with HE3286 or 0.1 mL vehicle (HERF405). The next day, mice were challenged with 50 μg of E-coli LPS under direct visualization of trachea under light anesthesia. Sixty minutes after the LPS challenge, mice were treated with a second dose of HE3286, or vehicle. Forty-eight hours after LPS challenge, mice were sacrificed and myeloperoxidase (MPO) activity in lungs determined as previously described [45]. Results are from two identical experiments. Data are expressed as O.D at 460 nM.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2984480&req=5

Figure 2: Effect of HE3286 treatment on MPO levels in LPS induced Lung Injury. On day-1, male C57 black/6 mice were pre-treated (gavage) with HE3286 or 0.1 mL vehicle (HERF405). The next day, mice were challenged with 50 μg of E-coli LPS under direct visualization of trachea under light anesthesia. Sixty minutes after the LPS challenge, mice were treated with a second dose of HE3286, or vehicle. Forty-eight hours after LPS challenge, mice were sacrificed and myeloperoxidase (MPO) activity in lungs determined as previously described [45]. Results are from two identical experiments. Data are expressed as O.D at 460 nM.
Mentions: The ability of HE3286 to reduce lung inflammation was also tested in the LPS-induced acute lung injury model. A meta-analysis of two independent studies revealed that when mice pre-treated with HE3286 (40 mg/kg) by oral gavage were challenged with 50 mg of LPS, levels of MPO in lungs at 48 hours were significantly (p < 0.025) reduced (~30%) compared to vehicle-treated animals (Figure 2). Reductions in MPO were also observed with HE3286 at lower doses (12 and 1.2 mg/kg), but as with inflammatory cells and cytokines (TNFa and IL-6) in bronchoalveolar lavage fluid (BAL), upon meta-analysis, these changes did not achieve statistical significance (data not shown).

Bottom Line: We tested the ability of this novel synthetic steroid with improved pharmacological properties to limit non-productive lung inflammation in rodents and attempted to gauge its immunological impact.When mice treated for two weeks with HE3286 were challenged with K. pneumoniae, nearly identical survival kinetics were observed in vehicle-treated, HE3286-treated and untreated groups.HE3286 represents a novel, first-in-class anti-inflammatory agent that may translate certain benefits of β-AET observed in rodents into treatments for chronic inflammatory pulmonary disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Harbor Biosciences, 9171 Towne Centre Drive, Suite 180, San Diego, CA 92122, USA. dauci@harborbiosciences.com.

ABSTRACT

Background: 17α-Ethynyl-5-androsten-3β, 7β, 17β-triol (HE3286) is a synthetic derivative of an endogenous steroid androstenetriol (β-AET), a metabolite of the abundant adrenal steroid deyhdroepiandrosterone (DHEA), with broad anti-inflammatory activities. We tested the ability of this novel synthetic steroid with improved pharmacological properties to limit non-productive lung inflammation in rodents and attempted to gauge its immunological impact.

Methods and results: In mice, oral treatment with HE3286 (40 mg/kg) significantly (p < 0.05) decreased neutrophil counts and exudate volumes (~50%) in carrageenan-induced pleurisy, and myeloperoxidase in lipopolysaccharide-induced lung injury. HE3286 (40 mg/kg) was not found to be profoundly immune suppressive in any of the classical animal models of immune function, including those used to evaluate antigen specific immune responses in vivo (ovalbumin immunization). When mice treated for two weeks with HE3286 were challenged with K. pneumoniae, nearly identical survival kinetics were observed in vehicle-treated, HE3286-treated and untreated groups.

Conclusions: HE3286 represents a novel, first-in-class anti-inflammatory agent that may translate certain benefits of β-AET observed in rodents into treatments for chronic inflammatory pulmonary disease.

No MeSH data available.


Related in: MedlinePlus