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Acute respiratory distress syndrome (ARDS) is a common respiratory critical syndrome with no effective therapeutic intervention. Neutrophils function in the overwhelming inflammatory process of acute lung injury (ALI) caused by ARDS; however, the phenotypic heterogeneity of pulmonary neutrophils in ALI/ARDS remains largely unknown. Here, using single-cell RNA sequencing, we identify two transcriptionally and functionally heterogeneous neutrophil populations (Fth1 hi Neu and Prok2 hi Neu) with distinct locations in LPS-induced ALI mouse lungs. Exposure to LPS promotes the Fth1 hi Neu subtype, with more inflammatory factors, stronger antioxidant, and decreased apoptosis under the regulation of interleukin-10. Furthermore, prolonged retention of Fth1 hi Neu within lung tissue aggravates inflammatory injury throughout the development of ALI/ARDS. Notably, ARDS patients have high ratios of Fth1 to Prok2 expression in pulmonary neutrophils, suggesting that the Fth1 hi Neu population may promote the pathological development and provide a marker of poor outcome. Acute respiratory distress syndrome (ARDS) is an acute pulmonary disease involving neutrophils. Here the authors characterise lung neutrophil infiltration during ARDS and show that there are neutrophils with different function and transcriptional profile which are regulated by IL-10.

Lipid metabolism involves multiple biological processes. As one of the most important lipid metabolic pathways, fatty acid oxidation (FAO) and its key rate-limiting enzyme, the carnitine palmitoyltransferase (CPT) system, regulate host immune responses and thus are of great clinical significance. The effect of the CPT system on different tissues or organs is complex: the deficiency or over-activation of CPT disrupts the immune homeostasis by causing energy metabolism disorder and inflammatory oxidative damage and therefore contributes to the development of various acute and chronic inflammatory disorders and cancer. Accordingly, agonists or antagonists targeting the CPT system may become novel approaches for the treatment of diseases. In this review, we first briefly describe the structure, distribution, and physiological action of the CPT system. We then summarize the pathophysiological role of the CPT system in chronic obstructive pulmonary disease, bronchial asthma, acute lung injury, chronic granulomatous disease, nonalcoholic fatty liver disease, hepatic ischemia–reperfusion injury, kidney fibrosis, acute kidney injury, cardiovascular disorders, and cancer. We are also concerned with the current knowledge in either preclinical or clinical studies of various CPT activators/inhibitors for the management of diseases. These compounds range from traditional Chinese medicines to novel nanodevices. Although great efforts have been made in studying the different kinds of CPT agonists/antagonists, only a few pharmaceuticals have been applied for clinical uses. Nevertheless, research on CPT activation or inhibition highlights the pharmacological modulation of CPT-dependent FAO, especially on different CPT isoforms, as a promising anti-inflammatory/antitumor therapeutic strategy for numerous disorders.

Background Mitochondrial damage leading to oxidant stress may play an important role in the pathogenesis of airflow obstruction and emphysema. NLPR3 inflammasome can be activated by mitochondrial ROS (mtROS) and other stimuli. We examined the importance of mtROS and NLRP3 inflammasome and their interactions in multiple ozone-induced lung inflammation and emphysema. Methods C57/BL6 mice were exposed to ozone (2.5 ppm, 3 h) or filtered air twice a week over 6 weeks. MitoTEMPO (20 mg/kg), an inhibitor of mtROS, and VX765 (100 mg/kg), an inhibitor of caspase-1 activity, were administered by intraperitoneal or intragastric injection respectively 1 h prior to each ozone exposure for 6 weeks. Results Ozone-exposed mice had increased bronchoalveolar lavage (BAL) total cells and levels of IL-1β, KC and IL-6, augmented lung tissue inflammation scores, enhanced oxidative stress with higher serum 8-OHdG concentrations, emphysema with greater mean linear intercept (Lm), airway remodeling with increased airway smooth muscle mass and airflow limitation as indicated by a reduction in the ratio of forced expiratory volume at 25 and 50 milliseconds to forced vital capacity (FEV 25 /FVC, FEV 50 /FVC). Both MitoTEMPO and VX765 reduced lung inflammation scores, cytokine levels, oxidative stress and increased mitochondrial fission proteins. VX765 also attenuated emphysema, airway remodeling and airflow limitation. MitoTEMPO inhibited the increased expression of mitochondrial complex II and IV and of NLPR3 while VX765 inhibited the expression and activity of NLRP3 and caspase-1 pathway in the lung. Conclusions Both mtROS and NLRP3 inflammasome play a role in ozone-induced lung inflammation while only NLRP3 is involved in ozone-induced emphysema.

Exposure to fine particulate matter (PM2.5) has been associated with lung inflammation and airway hyperresponsiveness (AHR). Transient receptor potential (TRP) vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) both may play important roles in lung inflammation and AHR. We investigated whether PM2.5-induced lung inflammation and AHR could be prevented by blocking TRPV1 and TRPA1 channels. Mice were injected intraperitoneally with AMG9810 (30 mg/kg, a TRPV1 antagonist) or A967079 (30 mg/kg, a TRPA1 antagonist) or their combination or vehicle (PBS) one hour before intranasal instillation of PM2.5 (7.8 mg/kg) or vehicle (PBS) for two consecutive days, and then the mice were studied 24 h later. All pretreatments inhibited PM2.5-induced AHR and inflammatory infiltration in the lung tissue and decreased inflammatory cytokine levels in the bronchoalveolar lavage fluid, together with oxidant levels in the lung. AMG9810 inhibited MFF expression and increased MFN2 expression while A967079 inhibited DRP1 expression and increased OPA1 expression; combined pretreatment reduced MFF and DPR1 expression and increased MFN2 and OPA1 expression. All pretreatments inhibited the activation of the TLR4/NF-κB pathway, while A967079 alone, and combined with AMG9810 also reduced the activation of the NLRP3/caspase-1 pathway. Both TRPV1 and TRPA1 channels play an important role in PM2.5-induced lung inflammation and AHR. However, inhibition of the TRPA1 channel or combined inhibition of TRPA1 and TRPV1 channels resulted in greater inhibitory effect on PM2.5-induced lung injury through regulating the mitochondrial fission/fusion proteins and inhibiting the TLR4/NF-κB and NLRP3/caspase-1 pathways.

Background: Mitochondrial dysfunction played a vital role in the pathogenesis of various diseases, including acute lung injury (ALI). However, few strategies targeting mitochondria were developed in treating ALI. Recently, we fabricated a porous Se@SiO2 nanoparticles (NPs) with antioxidant properties. Methods: The protective effect of Se@SiO2 NPs was assessed using confocal imaging, immunoblotting, RNA-seq, mitochondrial respiratory chain (MRC) activity assay, and transmission electron microscopy (TEM) in airway epithelial cell line (Beas-2B). The in vivo efficacy of Se@SiO2 NPs was evaluated in a lipopolysaccharide (LPS)-induced ALI mouse model. Results: This study demonstrated that Se@SiO2 NPs significantly increased the resistance of airway epithelial cells under oxidative injury and shifted lipopolysaccharide-induced gene expression profile closer to the untreated controls. The cytoprotection of Se@SiO2 was found to be achieved by maintaining mitochondrial function, activity, and dynamics. In an animal model of ALI, pretreated with the NPs improved mitochondrial dysfunction, thus reducing inflammatory responses and diffuse damage in lung tissues. Additionally, RNA-seq analysis provided evidence for the broad modulatory activity of our Se@SiO2 NPs in various metabolic disorders and inflammatory diseases. Conclusion: This study brought new insights into mitochondria-targeting bioactive NPs, with application potential in curing ALI or other human mitochondria-related disorders.

Acute respiratory distress syndrome (ARDS) is a common critical illness in respiratory care units with a huge public health burden. Despite tremendous advances in the prevention and treatment of ARDS, it remains the main cause of intensive care unit (ICU) management, and the mortality rate of ARDS remains unacceptably high. The poor performance of ARDS is closely related to its heterogeneous clinical syndrome caused by complicated pathophysiology. Based on the different pathophysiology phases, drugs, protective mechanical ventilation, conservative fluid therapy, and other treatment have been developed to serve as the ARDS therapeutic methods. In recent years, there has been a rapid development in nanomedicine, in which nanoparticles as drug delivery vehicles have been extensively studied in the treatment of ARDS. This study provides an overview of pharmacologic therapies for ARDS, including conventional drugs, natural medicine therapy, and nanomedicine. Particularly, we discuss the unique mechanism and strength of nanomedicine which may provide great promises in treating ARDS in the future.

Background Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common acute respiratory failure due to diffuse pulmonary inflammation and oedema. Elaborate regulation of macrophage activation is essential for managing this inflammatory process and maintaining tissue homeostasis. In the past decades, metabolic reprogramming of macrophages has emerged as a predominant role in modulating their biology and function. Here, we observed reduced expression of carnitine palmitoyltransferase 1A (CPT1A), a key rate‐limiting enzyme of fatty acid oxidation (FAO), in macrophages of lipopolysaccharide (LPS)‐induced ALI mouse model. We assume that CPT1A and its regulated FAO is involved in the regulation of macrophage polarization, which could be positive regulated by interleukin‐10 (IL‐10). Methods After nasal inhalation rIL‐10 and/or LPS, wild type (WT), IL‐10‐/‐, Cre‐CPT1Afl/fl and Cre+CPT1Afl/fl mice were sacrificed to harvest bronchoalveolar lavage fluid, blood serum and lungs to examine cell infiltration, cytokine production, lung injury severity and IHC. Bone marrow‐derived macrophages (BMDMs) were extracted from mice and stimulated by exogenous rIL‐10 and/or LPS. The qRT‐PCR, Seahorse XFe96 and FAO metabolite related kits were used to test the glycolysis and FAO level in BMDMs. Immunoblotting assay, confocal microscopy and fluorescence microplate were used to test macrophage polarization as well as mitochondrial structure and function damage. Results In in vivo experiments, we found that mice lacking CPT1A or IL‐10 produced an aggravate inflammatory response to LPS stimulation. However, the addition of rIL‐10 could alleviate the pulmonary inflammation in mice effectively. IHC results showed that IL‐10 expression in lung macrophage decreased dramatically in Cre+CPT1Afl/fl mice. The in vitro experiments showed Cre+CPT1Afl/fl and IL‐10‐/‐ BMDMs became more “glycolytic”, but less “FAO” when subjected to external attacks. However, the supplementation of rIL‐10 into macrophages showed reverse effect. CPT1A and IL‐10 can drive the polarization of BMDM from M1 phenotype to M2 phenotype, and CPT1A‐IL‐10 axis is also involved in the process of maintaining mitochondrial homeostasis. Conclusions CPT1A modulated metabolic reprogramming and polarisation of macrophage under LPS stimulation. The protective effects of CPT1A may be partly attributed to the induction of IL‐10/IL‐10 receptor expression. CPT1A modulated metabolic alteration and polarisation of macrophage under LPS stimulation. The protective effects of CPT1A may be partly attributed to the induction of interleukin‐10/interleukin‐10 receptor expression. The CPT1A‐IL‐10 axis and its regulated macrophage immunometabolism may provide a novel potential therapeutic targeting of ALI/ARDS.

Acute respiratory distress syndrome (ARDS) is a devastating respiratory disorder, characterized by overwhelming inflammation in the alveoli without effective pharmacological treatment. We aimed to investigate the effect and mechanism of angiotensin II type 2 receptor (AT2R) agonist, Compound 21 (C21), on the lipopolysaccharide (LPS)-induced acute lung injury (ALI) model. The protective effect of C21 was evaluated via enzyme-linked immunosorbent assay (ELISA), Western blot (WB), real-time PCR, and fluorescence microscopy in LPS-challenged THP1-derived macrophages. Besides, the in vivo efficacy of C21 was assessed using cell counting, ELISA, protein quantification, hematoxylin–eosin (H&E) staining, and WB in an LPS-induced ALI mouse model. The results showed that C21 significantly inhibited the secretion of pro-inflammatory cytokines (CCL-2, IL-6), overproduction of intracellular ROS, and activation of inflammatory pathways (NF-κB/NLRP3, p38/MAPK) in THP-1 cell-derived macrophages stimulated by LPS. In in vivo study, intraperitoneal injection of C21 could reduce airway leukocytes accumulation and chemokine/cytokine (keratinocyte chemoattractant (KC), IL-6) generation, as well as alleviate diffuse alveolar damage induced by LPS. Conclusively, the AT2R agonist C21 significantly inhibited LPS-stimulated excess inflammatory responses and oxidative stress in macrophages. Meanwhile, C21 could effectively alleviate acute inflammation and tissue damage in the lungs of ALI mice challenged by LPS. The results of this study bring new hope for the early treatment of ALI/ARDS.

Aqueous and photo stability of bixin are challenges in practical applications. Herein, transparent nanoemulsion can be self-emulsified to improve 9'-cis-bixin aqueous and photo stability. The 0.25 g carvacrol with 0.5% w/w 9'-cis-bixin, 2.08 g 12-% soybean lecithin, 2.25 g Tween 20, and 0.42 g water were mixed and stored overnight to fabricate transparent oil-in-water (O/W) nanoemulsion. The O/W nanoemulsion droplets had an average dimeter of 12.03 nm and equivalent spherical diameter of 6.78 nm. Photo stability of 9'-cis-bixin was improved after encapsulating in nanoemulsion droplets, demonstrated by significant improvement of 9'-cis-bixin degradation rate constant under ultraviolet. Nanoemulsion droplets significantly improved cell uptake of 9'-cis-bixin especially at the first 15 min after cocultivation of Caco-2 cells and 9'-cis-bixin encapsulated nanoemulsion. This study provides a comprehensive understanding of bixin protection by nanoemulsion fabricated by a self-emulsification method with potential cellular uptake.

Background: Mitochondrial dysfunction played a vital role in the pathogenesis of various diseases, including acute lung injury (ALI). However, few strategies targeting mitochondria were developed in treating ALI. Recently, we fabricated a porous Se@Si[O.sub.2] nanoparticles (NPs) with antioxidant properties. Methods: The protective effect of Se@Si[O.sub.2] NPs was assessed using confocal imaging, immunoblotting, RNA-seq, mitochondrial respiratory chain (MRC) activity assay, and transmission electron microscopy (TEM) in airway epithelial cell line (Beas-2B). The in vivo efficacy of Se@Si[O.sub.2] NPs was evaluated in a lipopolysaccharide (LPS)-induced ALI mouse model. Results: This study demonstrated that Se@Si[O.sub.2] NPs significantly increased the resistance of airway epithelial cells under oxidative injury and shifted lipopolysaccharide-induced gene expression profile closer to the untreated controls. The cytoprotection of Se@Si[O.sub.2] was found to be achieved by maintaining mitochondrial function, activity, and dynamics. In an animal model of ALI, pretreated with the NPs improved mitochondrial dysfunction, thus reducing inflammatory responses and diffuse damage in lung tissues. Additionally, RNA-seq analysis provided evidence for the broad modulatory activity of our Se@Si[O.sub.2] NPs in various metabolic disorders and inflammatory diseases. Conclusion: This study brought new insights into mitochondria-targeting bioactive NPs, with application potential in curing ALI or other human mitochondria-related disorders. Keywords: mitochondrial dysfunction, porous Se@Si[O.sub.2] nanoparticles, acute lung injury, anti-oxidative injury, anti-inflammation