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Avanafil as a Novel Therapeutic Agent Against LPS-Induced Acute Lung Injury via Increasing CGMP to Downregulate the TLR4-NF-κB-NLRP3 Inflammasome Signaling Pathway

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Abstract

Aim

We demonstrate the effect of PDE5 inhibitors in cases of acute lung injury via the relationship between cGMP/NO and the TLR4-NF-κB-NLRP3 pathway.

Materials and Methods

This study was performed with 30 male Wistar albino rats. Lipopolysaccharide (LPS) was administered intratracheally to the rats and acute lung injury (ALI) was induced. Twelve hours after LPS administration, avanafil, prepared at suitable doses according to the body weights of the animals, was administered by oral gavage. Lung tissue samples of all groups were examined histopathologically and by immunochemical staining (IL-1β, iNOS, TLR4, and NF-κB). The iNOS, NLRP3, and IL-1B mRNA expression levels in the lung tissues were measured by RT-PCR. The left upper lobes of the rat lungs were dried at 70 °C for 48 h and lung water content was calculated.

Result

Statistically significant increases in iNOS, NLRP3, and IL-1β mRNA expressions were observed in the rats with ALI compared to the healthy controls (p < 0.0001). Those increased expressions were reduced at both doses of avanafil (p < 0.0001). This reduction was found to be greater at 20 mg/kg (p < 0.0001). IL-1β, iNOS, TLR4, and NF-κB immunopositivity was moderate/severe in the ALI group and mild in the group with ALI + avanafil at 20 mg/kg (p < 0.05). When the wet/dry lung ratios were calculated, a statistically significant increase was seen in the ALI group compared to the healthy rats (p < 0.05). That increase was decreased with both avanafil doses (p < 0.05).

Conclusion

We suggest that avanafil may prevent the progression of ALI and be effective in its treatment. We hope that this study will be supported by future clinical studies to yield a new indication for avanafil.

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Authors and Affiliations

  1. Department of Anesthesiology and Reanimation, Educational and Research Hospital, Erzurum, Turkey

    Pelin Aydin

  2. Department of Pharmacology, Faculty of Medicine, Ataturk University, Ataturk University Campus, Ataturk District, Erzurum, 25240, Yakutiye, Turkey

    Pelin Aydin, Zeynep Berna Aksakalli Magden, Hamza Halici, Nurullah Akgun & Elif Cadirci

  3. Department of Health Services Vocational School, Bayburt University, Bayburt, Turkey

    Sevgi Karabulut Uzuncakmak

  4. Department of Hınıs Vocational Training School, Ataturk University, Erzurum, Turkey

    Hamza Halici

  5. Department of Pathology, Faculty of Veterinary Medicine, Erciyes University, Kayseri, Turkey

    Ali Sefa Mendil

  6. Department of Pathology, Faculty of Veterinary Medicine, Ataturk University, Erzurum, Turkey

    Behzad Mokhtare

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  1. Pelin Aydin
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Contributions

PA. contributed to the literature review, design, writing of the main manuscript. ZBAM.contributed to the literature review, data collection and/or processing. SKU.contributed to the design, analysis and/or interpretation. HH.contributed to the analysis and/or interpretation, and preparation of figures 1-4. NA. contributed to the preparation of tables 1 and 2. ASM.contributed to the data collection and/or processing. BM. contributed to the data collection and/or processing. EC. contributed to the critical review. All authors reviewed the manuscript.

Corresponding author

Correspondence to Pelin Aydin.

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Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethical Approval

The study was approved by the Local Ethics Committee of Ataturk University (Local Ethics Council of Animal Experiments, Protocol No: 09.07.2021 issue number E-42190979–000-2100184052).

Informed Consent

Not Applicable.

Research Involving Animal Rights

All animal procedures and experiments were performed according to national guidelines for laboratory animals’ use and care and the European Community Council Directives (2010/63/EU).

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Aydin, P., Magden, Z.B.A., Uzuncakmak, S.K. et al. Avanafil as a Novel Therapeutic Agent Against LPS-Induced Acute Lung Injury via Increasing CGMP to Downregulate the TLR4-NF-κB-NLRP3 Inflammasome Signaling Pathway. Lung 200, 561–572 (2022). https://doi.org/10.1007/s00408-022-00564-9

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