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
Aydin, Pelin, Magden, Zeynep Berna Aksakalli, Uzuncakmak, Sevgi Karabulut, Halici, Hamza, Akgun, Nurullah, Mendil, Ali Sefa, Mokhtare, Behzad, Cadirci, Elif
Aim We demonstrate the effect of PDE5 inhibitors in cases of acute lung injury via the relationship between cGMP/NO and the TLR4-NF-kappa B-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-1 beta, iNOS, TLR4, and NF-kappa B). 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 degrees C for 48 h and lung water content was calculated. Result Statistically significant increases in iNOS, NLRP3, and IL-1 beta 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-1 beta, iNOS, TLR4, and NF-kappa B 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.
- Journal
- LUNG
- Year
- 2022
- Volume
- 200
- Issue
- 5
- Pages
- 561-572
- ISSN
- 0341-2040
- eISSN
- 1432-1750
- DOI
- 10.1007/s00408-022-00564-9
- WoS UID
- WOS:000847659000001