All‑trans retinoic acid promotes macrophage phagocytosis and decreases inflammation via inhibiting CD14/TLR4 in acute lung injury

Abstract

Acute lung injury (ALI) is a common clinical emergency and all-trans retinoic acid (ATRA) can alleviate organ injury. Therefore, the present study investigated the role of ATRA in ALI. Lipopolysaccharide (LPS)-induced ALI rats were treated with ATRA and the arterial partial pressure of oxygen (PaO 2 ), lung wet/dry weight (W/D) ratio and protein content in the bronchial alveolar lavage fluid (BALF) were measured to evaluate the effect of ATRA on ALI rats. Alveolar macrophages were isolated from the BALF. The phagocytic function of macrophages was detected using the chicken erythrocyte phagocytosis method and flow cytometry. The viability of macrophages was measured using a Cell Counting Kit-8 assay, and apoptosis was analyzed using a TUNEL assay and flow cytometry. The expression levels of Toll-like receptor 4 (TLR4) and cluster of differentiation (CD)14 on the macrophage membrane were detected by immunofluorescence staining. The protein levels of TLR4, CD14, phosphorylated (p)-65, p65, p-IκBα and IκBα were analyzed using western blotting. The concentrations of IL-6, IL-1β and macrophage inflammatory protein-2 in the plasma of rats were detected by ELISA. Macrophages were treated with IAXO-102 (TLR4 inhibitor) to verify the involvement of CD14/TLR4 in the effect of ATRA on ALI. ATRA provided protection against LPS-induced ALI, as evidenced by the increased PaO 2 and reduced lung W/D ratio and protein content in the BALF. ATRA enhanced macrophage phagocytosis and viability and reduced apoptosis and inflammation in ALI rats. Mechanically, ATRA inhibited CD14 and TLR4 expression and NF-κB pathway activation. ATRA enhanced macrophage phagocytosis and reduced inflammation by inhibiting the CD14/TLR4-NF-κB pathway in LPS-induced ALI. In summary, ATRA inactivated the NF-κB pathway by inhibiting the expression of CD14/TLR4 receptor in the alveolar macrophages of rats, thus enhancing the phagocytic function of macrophages in ALI rats, improving the activity of macrophages, inhibiting apoptosis, reducing the levels of inflammatory factors, and consequently playing a protective role in ALI model rats. This study may offer novel insights for the clinical management of ALI.

Efficacy of terpenoids in attenuating pulmonary edema in acute lung injury: A meta-analysis of animal studies

“…After reviewing all of the publications, 10 studies were excluded because of missing outcome data ( Ehrhart et al, 2000 ; Tawadros et al, 2007 ; Nader and Baraka, 2012 ; An et al, 2014 ; Wang et al, 2015 ; Liu and Chen, 2016 ; Shen et al, 2017 ; Ni et al, 2019 ; Wang et al, 2019 ; Yang et al, 2019 ), and another 12 studies were excluded because multiple interventions were investigated ( Murakami et al, 2000 ; Lin et al, 2011 ; Li et al, 2014b ; Li et al, 2016a ; Li et al, 2016b ; Baradaran Rahimi et al, 2019 ; Ye et al, 2019 ; Duan et al, 2020 ; Yue et al, 2020 ; Choi et al, 2021 ; Zhang et al, 2021 ; Liu et al, 2022 ). In conclusion, 16 studies were included in this meta-analysis, as described below ( Shi et al, 2007 ; Yang et al, 2011 ; Chen et al, 2014 ; Yang et al, 2014 ; Yuan et al, 2014 ; Wei and Wang, 2017 ; Li et al, 2018a ; Li et al, 2018b ; Luo et al, 2019 ; Ren et al, 2019 ; Zhang et al, 2020 ; Ali et al, 2021 ; Dikmen et al, 2021 ; Li et al, 2021 ; Wang et al, 2021 ; Wu et al, 2021 ) ( Figure 1 ).…”

“…Rats ranged in age from 6 to 8 weeks and in weight from 90 to 350 g. In terms of intervention, diterpenoid, monoterpenoid, sesquiterpenoid, and triterpenoid were used in seven studies ( Shi et al, 2007 ; Yang et al, 2011 ; Yang et al, 2014 ; Wei and Wang, 2017 ; Li et al, 2018a ; Li et al, 2018b ; Luo et al, 2019 ), three studies ( Yuan et al, 2014 ; Ren et al, 2019 ; Li et al, 2021 ), two studies ( Ali et al, 2021 ; Wang et al, 2021 ), and four studies ( Chen et al, 2014 ; Zhang et al, 2020 ; Dikmen et al, 2021 ; Wu et al, 2021 ), respectively. In addition, 13 studies used male rats ( Shi et al, 2007 ; Yang et al, 2011 ; Chen et al, 2014 ; Yang et al, 2014 ; Yuan et al, 2014 ; Wei and Wang, 2017 ; Li et al, 2018a ; Luo et al, 2019 ; Ren et al, 2019 ; Zhang et al, 2020 ; Dikmen et al, 2021 ; Li et al, 2021 ; Wang et al, 2021 ), whereas three studies did not report gender ( Li et al, 2018b ; Ali et al, 2021 ; Wu et al, 2021 ). Sprague Dawley rats were used in 11 studies ( Shi et al, 2007 ; Yang et al, 2014 ; Wei and Wang, 2017 ; Li et al, 2018a ; Li et al, 2018b ; Luo et al, 2019 ; Ren et al, 2019 ; Ali et al, 2021 ; Li et al, 2021 ; Wang et al, 2021 ; Wu et al, 2021 ) and Wistar rats in five studies ( Yang et al, 2011 ; Chen et al, 2014 ; Yuan et al, 2014 ; Zhang et al, 2020 ; Dikmen et al, 2021 ).…”

“…In addition, 13 studies used male rats ( Shi et al, 2007 ; Yang et al, 2011 ; Chen et al, 2014 ; Yang et al, 2014 ; Yuan et al, 2014 ; Wei and Wang, 2017 ; Li et al, 2018a ; Luo et al, 2019 ; Ren et al, 2019 ; Zhang et al, 2020 ; Dikmen et al, 2021 ; Li et al, 2021 ; Wang et al, 2021 ), whereas three studies did not report gender ( Li et al, 2018b ; Ali et al, 2021 ; Wu et al, 2021 ). Sprague Dawley rats were used in 11 studies ( Shi et al, 2007 ; Yang et al, 2014 ; Wei and Wang, 2017 ; Li et al, 2018a ; Li et al, 2018b ; Luo et al, 2019 ; Ren et al, 2019 ; Ali et al, 2021 ; Li et al, 2021 ; Wang et al, 2021 ; Wu et al, 2021 ) and Wistar rats in five studies ( Yang et al, 2011 ; Chen et al, 2014 ; Yuan et al, 2014 ; Zhang et al, 2020 ; Dikmen et al, 2021 ).…”

“…LPS was administered intravenously in seven studies ( Yang et al, 2011 ; Yang et al, 2014 ; Wei and Wang, 2017 ; Li et al, 2018a ; Li et al, 2018b ; Luo et al, 2019 ; Dikmen et al, 2021 ), intraperitoneally in one study ( Shi et al, 2007 ), and intratracheally in eight studies ( Chen et al, 2014 ; Yuan et al, 2014 ; Ren et al, 2019 ; Zhang et al, 2020 ; Ali et al, 2021 ; Li et al, 2021 ; Wang et al, 2021 ; Wu et al, 2021 ). The LPS dosage ranged from 0.1 to 10 mg/kg.…”

“…The LPS dosage ranged from 0.1 to 10 mg/kg. Terpenoid was administered intragastrically in four studies ( Chen et al, 2014 ; Yang et al, 2014 ; Yuan et al, 2014 ; Zhang et al, 2020 ), intravenously in three studies ( Yang et al, 2011 ; Dikmen et al, 2021 ; Wang et al, 2021 ), intraperitoneally in eight studies ( Shi et al, 2007 ; Wei and Wang, 2017 ; Li et al, 2018a ; Li et al, 2018b ; Luo et al, 2019 ; Ren et al, 2019 ; Ali et al, 2021 ; Wu et al, 2021 ), and intratracheally in one study ( Li et al, 2021 ). The terpenoid dosage ranged from 0.08 to 370 μmol/kg.…”