Abstract
Background: Pulmonary fibrosis (PF) is a chronic, progressive, and, ultimately, terminal interstitial disease caused by a variety of factors, ranging from genetics, bacterial, and viral infections, to drugs and other influences. Varying degrees of PF and its rapid progress have been widely reported in post-COVID-19 patients and there is consequently an urgent need to develop an appropriate, cost-effective approach for the prevention and management of PF. Aim: The potential “therapeutic” effect of the tocotrienol-rich fraction (TRF) and carotene against bleomycin (BLM)-induced lung fibrosis was investigated in rats via the modulation of TGF-β/Smad, PI3K/Akt/mTOR, and NF-κB signaling pathways. Design/Methods: Lung fibrosis was induced in Sprague-Dawley rats by a single intratracheal BLM (5 mg/kg) injection. These rats were subsequently treated with TRF (50, 100, and 200 mg/kg body wt/day), carotene (10 mg/kg body wt/day), or a combination of TRF (200 mg/kg body wt/day) and carotene (10 mg/kg body wt/day) for 28 days by gavage administration. A group of normal rats was provided with saline as a substitute for BLM as the control. Lung function and biochemical, histopathological, and molecular alterations were studied in the lung tissues. Results: Both the TRF and carotene treatments were found to significantly restore the BLM-induced alterations in anti-inflammatory and antioxidant functions. The treatments appeared to show pneumoprotective effects through the upregulation of antioxidant status, downregulation of MMP-7 and inflammatory cytokine expressions, and reduction in collagen accumulation (hydroxyproline). We demonstrated that TRF and carotene ameliorate BLM-induced lung injuries through the inhibition of apoptosis, the induction of TGF-β1/Smad, PI3K/Akt/mTOR, and NF-κB signaling pathways. Furthermore, the increased expression levels were shown to be significantly and dose-dependently downregulated by TRF (50, 100, and 200 mg/kg body wt/day) treatment in high probability. The histopathological findings further confirmed that the TRF and carotene treatments had significantly attenuated the BLM-induced lung injury in rats. Conclusion: The results of this study clearly indicate the ability of TRF and carotene to restore the antioxidant system and to inhibit proinflammatory cytokines. These findings, thus, revealed the potential of TRF and carotene as preventive candidates for the treatment of PF in the future.
Highlights
The severe acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was first reported from Wuhan, China, in December2019 [1], has spread rapidly to become a global pandemic, with more than 260 million confirmed infections and almost 5.2 million deaths reported by the World Health Organization (WHO) as of 28 November 2021
Interstitial pneumonia is a common feature of COVID-19 and can be complicated by acute respiratory distress syndrome (ARDS), of which pulmonary fibrosis (PF) is a recognized sequela [3]
Tocotrienol-rich fraction (TRF) and natural mixed-carotene complex 20% oil concentrate samples were obtained from the Malaysian Palm Oil Board (MPOB)
Summary
The severe acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was first reported from Wuhan, China, in December2019 [1], has spread rapidly to become a global pandemic, with more than 260 million confirmed infections and almost 5.2 million deaths reported by the World Health Organization (WHO) as of 28 November 2021. The severe acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was first reported from Wuhan, China, in December. More than 230 million people worldwide were registered as having recovered from COVID-19, long-term pulmonary complications remain a concern [2], while the spread of the pandemic continues. Interstitial pneumonia is a common feature of COVID-19 and can be complicated by acute respiratory distress syndrome (ARDS), of which pulmonary fibrosis (PF) is a recognized sequela [3]. Fibrotic changes have been reported in patients experiencing severe or long-term COVID-19, as well as in the pulmonary postmortems of patients with COVID-19 [4]. Within the gravity of the pandemic, the burden of fibrotic lung disease following SARS-CoV-2 infection is considered high, and approximately 47% of COVID-19 patients have been reported to suffer impaired gas transfer consistent with pulmonary fibrosis or associated vasculopathy [5].
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