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Inducing Acute Lung Injury in Mice by Direct Intratracheal Lipopolysaccharide Instillation
Published on: July 6, 2019
Nootkatone mitigates LPS-induced acute lung injury by modulating the NF-κB and Nrf2 pathways in mice
D D V Hanuman1, Anil Kumar Banothu1, Kala Kumar Bharani1
1Department of Veterinary Pharmacology and Toxicology, College of Veterinary Science, P.V. Narsimha Rao Telangana Veterinary University, Hyderabad, India.
Abstract:
Acute lung injury is a serious condition that can be life-threatening. Nootkatone, a promising phytochemical, possesses notable antioxidant and anti-inflammatory properties. The current study aimed to investigate the anti-inflammatory effects of nootkatone both in vitro using Raw 264.7 macrophages and in vivo through intraperitoneal administration at doses of 50 and 100 mg/kg for 7 days. Animals were divided into five groups: normal control (NC), disease control (DC; LPS 10 μg/kg, oropharyngeal), nootkatone low dose (NLD; 50 mg/kg, i.p. for 7 days + LPS), nootkatone high dose (NHD; 100 mg/kg, i.p. for 7 days + LPS), and nootkatone per se (NPS; 100 mg/kg nootkatone alone). The study assessed the efficacy of nootkatone against lipopolysaccharide (LPS)-induced lung injury in mice, with LPS administered via the oropharyngeal route at 10 μg/kg. Concentrations of nootkatone up to 50 μM were found to be safe, showing only a modest reduction in cell viability. Treatment with various doses of nootkatone effectively mitigated LPS-induced inflammation in Raw 264.7 macrophage cells, as indicated by modulation of inflammatory cytokines such as IL-10 and TNF-α. We observed significant (p < 0.05) alteration in absolute and relative lung weights, as well as in hematological profiles. The levels of cytokines (IL-6, TNF-α, IL-1β, IL-22; IL-17; IFN-γ; TGF-β1, and IL-10) were significantly modulated in the NLD (50 mg/kg) and NHD (100 mg/kg) groups. Furthermore, the levels of malondialdehyde and nitrite were significantly lower in these groups compared to the disease control. Histological analysis revealed the reversal of lung tissue damage in the treated group compared to the disease control group. Notably, immunohistochemical evaluation of Nrf-2, NF-κB, TNF-α, and COX-2 expression further confirmed the potent anti-inflammatory effects of nootkatone. This study provides comprehensive evidence that nootkatone may represent a promising candidate for further research in the management of pulmonary inflammation.
Insights
Nootkatone demonstrates significant anti-inflammatory effects against acute lung injury in mice. This study shows nootkatone reduces inflammation and lung damage, suggesting its potential for treating pulmonary inflammation.
Area of Science:
- Pharmacology and Toxicology
- Immunology
- Respiratory Medicine
Background:
- Acute lung injury (ALI) is a severe, life-threatening condition.
- Nootkatone, a phytochemical, exhibits antioxidant and anti-inflammatory properties.
- Investigating nootkatone's efficacy against lipopolysaccharide (LPS)-induced ALI is crucial.
Purpose of the Study:
- To evaluate the anti-inflammatory effects of nootkatone in an in vitro macrophage model and an in vivo mouse model of ALI.
- To assess the safety and therapeutic potential of nootkatone in managing pulmonary inflammation.
Main Methods:
- In vitro studies used Raw 264.7 macrophages treated with nootkatone.
- In vivo studies involved intraperitoneal administration of nootkatone (50 and 100 mg/kg) to mice for 7 days prior to LPS-induced ALI.
- Evaluations included cytokine levels, lung/hematological parameters, oxidative stress markers, histology, and immunohistochemistry (Nrf-2, NF-κB, TNF-α, COX-2).
Main Results:
- Nootkatone (up to 50 μM) showed safety in macrophages.
- Nootkatone treatment significantly modulated inflammatory cytokines (IL-10, TNF-α, IL-6, etc.), reduced lung weights, and improved hematological profiles.
- Reduced malondialdehyde and nitrite levels, histological evidence of lung tissue repair, and favorable Nrf-2/NF-κB pathway modulation were observed.
Conclusions:
- Nootkatone effectively mitigates LPS-induced pulmonary inflammation and lung injury in mice.
- The compound demonstrates potent anti-inflammatory effects, likely mediated through antioxidant pathways and modulation of key inflammatory markers.
- Nootkatone is a promising candidate for further research and development in the treatment of pulmonary inflammation.
