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PARP is activated in human asthma and its inhibition by olaparib blocks house dust mite-induced disease in mice.

Ghonim MA, Pyakurel K, Ibba SV, Wang J, Rodriguez P, Al-Khami AA, Lammi MR, Kim H, Zea AH, Davis C, Okpechi S, Wyczechowska D, Al-Ghareeb K, Mansy MS, Ochoa A, Naura AS, Boulares AH - Clin. Sci. (2015)

Bottom Line: Our results show that PARP is activated in PBMCs and lung tissues of asthmatics.These effects were linked to a marked reduction in T helper 2 (Th2) cytokine production without a prominent effect on interferon (IFN)-γ or interleukin (IL)-10.In CD3/CD28-stimulated human CD4 (+)T-cells, olaparib treatment reduced Th2 cytokine production potentially by modulating GATA binding protein-3 (gata-3)/IL-4 expression while moderately affecting T-cell proliferation.

View Article: PubMed Central - PubMed

Affiliation: The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, U.S.A. Microbiology and Immunology Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11651, Egypt.

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PARP inhibition by olaparib or gene knockout blocks asthma-like traits in chronically HDM-exposed miceC57BL/6J WT or PARP-1−/− mice were subjected to HDM challenge or left untreated. HDM-challenged WT mice received 5 mg/kg of olaparib or saline once (S) 30 min after the last HDM challenge or once daily for 3 days (M). All mice were killed 48h later and BALF and organs were collected. (A) Cells of BALF were differentially stained and total eosinophils, macrophages, lymphocytes and neutrophils were counted. Data are expressed as total number of cells per mouse. (B) WT mice were subjected to HDM challenge followed by an i.p. injection of saline (▲), single (◆) or multiple administrations of 5 mg/kg olaparib (○). Control mice were not sensitized or challenged (●). PARP-1−/− mice were also subjected to HDM challenge (▼) and control mice were left unchallenged (■). Penh was recorded 24 h later using a whole body plethysmograph system before and after the indicated concentrations of aerosolized methacholine (MeCh). Results are plotted as maximal fold increase in Penh relative to baseline and expressed as mean ± S.E.M., where n=6 mice per group. *Difference from control WT mice, P<0.01; #Difference from HDM-challenged WT mice, P<0.01; ¶Difference from HDM-challenged WT mice that received a single dose of olaparib, P<0.01.
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Figure 2: PARP inhibition by olaparib or gene knockout blocks asthma-like traits in chronically HDM-exposed miceC57BL/6J WT or PARP-1−/− mice were subjected to HDM challenge or left untreated. HDM-challenged WT mice received 5 mg/kg of olaparib or saline once (S) 30 min after the last HDM challenge or once daily for 3 days (M). All mice were killed 48h later and BALF and organs were collected. (A) Cells of BALF were differentially stained and total eosinophils, macrophages, lymphocytes and neutrophils were counted. Data are expressed as total number of cells per mouse. (B) WT mice were subjected to HDM challenge followed by an i.p. injection of saline (▲), single (◆) or multiple administrations of 5 mg/kg olaparib (○). Control mice were not sensitized or challenged (●). PARP-1−/− mice were also subjected to HDM challenge (▼) and control mice were left unchallenged (■). Penh was recorded 24 h later using a whole body plethysmograph system before and after the indicated concentrations of aerosolized methacholine (MeCh). Results are plotted as maximal fold increase in Penh relative to baseline and expressed as mean ± S.E.M., where n=6 mice per group. *Difference from control WT mice, P<0.01; #Difference from HDM-challenged WT mice, P<0.01; ¶Difference from HDM-challenged WT mice that received a single dose of olaparib, P<0.01.

Mentions: We next examined whether PARP inhibition pharmacologically by olaparib or genetically by gene knockout blocks asthma-like manifestation upon intraneural (i.n.) administration of HDM. Figure 2 (A) shows that a single administration of olaparib at the end of the HDM exposure protocol was highly effective in decreasing recruitment of eosinophils and macrophages as well as overall cellularity in the lungs. However, the increase in the number of lymphocytes was not affected. A remarkable protection was achieved upon two additional administrations of the drug including a reduction in the number of lymphocytes. Similar results were observed in HDM-exposed PARP-1−/− mice, which provide evidence for the specificity of such protective effects. Interestingly, repeated administration of olaparib provided significantly better reduction in recruitment of the total number of inflammatory cells, eosinophils and macrophages, than that provided by PARP-1 gene deletion.


PARP is activated in human asthma and its inhibition by olaparib blocks house dust mite-induced disease in mice.

Ghonim MA, Pyakurel K, Ibba SV, Wang J, Rodriguez P, Al-Khami AA, Lammi MR, Kim H, Zea AH, Davis C, Okpechi S, Wyczechowska D, Al-Ghareeb K, Mansy MS, Ochoa A, Naura AS, Boulares AH - Clin. Sci. (2015)

PARP inhibition by olaparib or gene knockout blocks asthma-like traits in chronically HDM-exposed miceC57BL/6J WT or PARP-1−/− mice were subjected to HDM challenge or left untreated. HDM-challenged WT mice received 5 mg/kg of olaparib or saline once (S) 30 min after the last HDM challenge or once daily for 3 days (M). All mice were killed 48h later and BALF and organs were collected. (A) Cells of BALF were differentially stained and total eosinophils, macrophages, lymphocytes and neutrophils were counted. Data are expressed as total number of cells per mouse. (B) WT mice were subjected to HDM challenge followed by an i.p. injection of saline (▲), single (◆) or multiple administrations of 5 mg/kg olaparib (○). Control mice were not sensitized or challenged (●). PARP-1−/− mice were also subjected to HDM challenge (▼) and control mice were left unchallenged (■). Penh was recorded 24 h later using a whole body plethysmograph system before and after the indicated concentrations of aerosolized methacholine (MeCh). Results are plotted as maximal fold increase in Penh relative to baseline and expressed as mean ± S.E.M., where n=6 mice per group. *Difference from control WT mice, P<0.01; #Difference from HDM-challenged WT mice, P<0.01; ¶Difference from HDM-challenged WT mice that received a single dose of olaparib, P<0.01.
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Figure 2: PARP inhibition by olaparib or gene knockout blocks asthma-like traits in chronically HDM-exposed miceC57BL/6J WT or PARP-1−/− mice were subjected to HDM challenge or left untreated. HDM-challenged WT mice received 5 mg/kg of olaparib or saline once (S) 30 min after the last HDM challenge or once daily for 3 days (M). All mice were killed 48h later and BALF and organs were collected. (A) Cells of BALF were differentially stained and total eosinophils, macrophages, lymphocytes and neutrophils were counted. Data are expressed as total number of cells per mouse. (B) WT mice were subjected to HDM challenge followed by an i.p. injection of saline (▲), single (◆) or multiple administrations of 5 mg/kg olaparib (○). Control mice were not sensitized or challenged (●). PARP-1−/− mice were also subjected to HDM challenge (▼) and control mice were left unchallenged (■). Penh was recorded 24 h later using a whole body plethysmograph system before and after the indicated concentrations of aerosolized methacholine (MeCh). Results are plotted as maximal fold increase in Penh relative to baseline and expressed as mean ± S.E.M., where n=6 mice per group. *Difference from control WT mice, P<0.01; #Difference from HDM-challenged WT mice, P<0.01; ¶Difference from HDM-challenged WT mice that received a single dose of olaparib, P<0.01.
Mentions: We next examined whether PARP inhibition pharmacologically by olaparib or genetically by gene knockout blocks asthma-like manifestation upon intraneural (i.n.) administration of HDM. Figure 2 (A) shows that a single administration of olaparib at the end of the HDM exposure protocol was highly effective in decreasing recruitment of eosinophils and macrophages as well as overall cellularity in the lungs. However, the increase in the number of lymphocytes was not affected. A remarkable protection was achieved upon two additional administrations of the drug including a reduction in the number of lymphocytes. Similar results were observed in HDM-exposed PARP-1−/− mice, which provide evidence for the specificity of such protective effects. Interestingly, repeated administration of olaparib provided significantly better reduction in recruitment of the total number of inflammatory cells, eosinophils and macrophages, than that provided by PARP-1 gene deletion.

Bottom Line: Our results show that PARP is activated in PBMCs and lung tissues of asthmatics.These effects were linked to a marked reduction in T helper 2 (Th2) cytokine production without a prominent effect on interferon (IFN)-γ or interleukin (IL)-10.In CD3/CD28-stimulated human CD4 (+)T-cells, olaparib treatment reduced Th2 cytokine production potentially by modulating GATA binding protein-3 (gata-3)/IL-4 expression while moderately affecting T-cell proliferation.

View Article: PubMed Central - PubMed

Affiliation: The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, U.S.A. Microbiology and Immunology Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11651, Egypt.

Show MeSH
Related in: MedlinePlus