Therapeutic potential of proteases in acute lung injury and respiratory distress syndrome via TLR4/Nrf2/NF-kB...

Area of Science:

• Biochemistry
• Pharmacology
• Pulmonology

Background:

• Acute lung injury (ALI) and respiratory distress syndrome (ARDS) are critical complications, particularly highlighted during the COVID-19 pandemic.
• Protease enzymes exhibit diverse therapeutic properties, including antioxidant, anti-inflammatory, antifibrotic, and fibrinolytic activities.
• Lipopolysaccharide (LPS) is a potent inducer of ALI, often mediated through Toll-like receptor 4 (TLR-4).

Purpose of the Study:

• To evaluate the therapeutic potential of bacterial protease and chymotrypsin in mitigating LPS-induced ALI in a rat model.
• To investigate the molecular mechanisms, including the inhibition of TLR-4, by these proteases using molecular docking.

Main Methods:

• Acute lung injury was induced in rats using lipopolysaccharide (LPS).
• Treatment groups received either bacterial protease or chymotrypsin.
• Molecular docking simulations were performed to assess the inhibitory effects on TLR-4.
• Key molecular markers including TLR-4, Nrf2, p38 MAPK, NF-kB, IKK-β, TGF-β, caspase-3, and VEGF were analyzed.

Main Results:

• Bacterial protease treatment normalized levels of TLR-4, Nrf2, p38 MAPK, NF-kB, and IKK-β.
• Chymotrypsin treatment normalized levels of TLR-4, IKK-β, IL-6, and IL-17.
• Both proteases significantly reduced the expression of TGF-β, caspase-3, and VEGF.
• Bacterial protease demonstrated superior effects on oxidative stress, edema, and fibrosis.
• Chymotrypsin showed better efficacy in the acute phase and modulation of innate immunity.

Conclusions:

• Both bacterial protease and chymotrypsin effectively ameliorate LPS-induced acute lung injury in rats.
• These proteases modulate the critical TLR4/Nrf2/NF-kB signaling pathway.
• Each protease exhibits distinct mechanisms, offering unique therapeutic advantages for ALI and ARDS.