Reduce Lung Injury Research Articles

Comparative Genomics Uncovers Molecular Adaptations for Cetacean Deep-Sea Diving.

Cetaceans show remarkable diversity in diving capability, implying a range of adaptive strategies to hazards such as hydrostatic pressure and oxidative stress, but few studies have considered the evolution of extreme diving. Here, we first examined the relationship between morphological and physiological factors and diving capability and then considered the molecular evolution of candidate deep-sea diving traits in a genomic dataset of cetaceans. Our dataset included six super-divers, sperm whales (families Physeteridae and Kogiidae) and beaked whales (Ziphiidae), species that can dive deeper than 1000 m for about an hour or longer. We found a positive association between diving capability and oxygen-linked globins, and super-diver myoglobin (MB) is under positive selection and harbours a reported functional amino acid change. Blubber thickness was positively associated, likely to provide thermal insulation and hydrostatic pressure resistance. Super-divers have gene changes that may contribute to differences in the composition of outer blubber neutral lipids (triacylglycerols and wax esters), fatty acids and cholesterol. Total lung capacity relative to body mass showed a negative association, ostensibly to limit gas bubbles that can cause decompression sickness. A functional assay suggests that an ATP8B1 amino acid substitution may reduce lung injury in super-divers. Super-diver XDH has two unique amino acids and a decreased ability to produce uric acid under hypoxia when its ROS-generating XO isoform is prevalent, suggesting that it reduces cell damage from oxidative stress and uric acid accumulation in species with prolonged dives. Our study deepens the understanding of how deep-sea diving emerged in the cetacean lineage.

Chitosan Nanoparticle-Encapsulated Cordyceps militaris Grown on Germinated Rhynchosia nulubilis Reduces Type II Alveolar Epithelial Cell Apoptosis in PM2.5-Induced Lung Injury

Chitosan nanoparticles (CNPs) were synthesized in this study to enhance the limited bioactivity and stability of Cordyceps militaris grown on germinated Rhynchosia nulubilis (GRC) and effectively deliver it to target tissues. Under optimized conditions, stable encapsulation of GRC was achieved by setting the chitosan (CHI)-to-tripolyphosphate (TPP) ratio to 4:1 and adjusting the pH of TPP to 2, resulting in a zeta potential of +22.77 mV, which indicated excellent stability. As the concentration of GRC increased, the encapsulation efficiency decreased, whereas the loading efficiency increased. Fourier-transform infrared (FT-IR) spectroscopy revealed shifts in the amide I and II bands of CHI from 1659 and 1578 to 1639 cm⁻1, indicating hydrogen bonding and successful encapsulation of GRC encapsulated with CNPs (GCN). X-ray diffraction (XRD) examination revealed the transition of the nanoparticles from a crystalline to an amorphous state, further confirming successful encapsulation. In vivo experiments demonstrated that GCN treatment significantly reduced lung injury scores in fine particulate matter (PM2.5)-exposed mice (p < 0.05) and alleviated lung epithelial barrier damage by restoring the decreased expression of occludin protein (p < 0.05). In addition, GCN decreased the PM2.5-induced upregulation of MMP-9 and COL1A1 mRNA expression levels, preventing extracellular matrix (ECM) degradation and collagen accumulation (p < 0.05). GCN exhibited antioxidant effects by reducing the mRNA expression of nitric oxide synthase (iNOS) and enhancing both the protein and mRNA expression of superoxide dismutase (SOD-1) caused by PM2.5, thereby alleviating oxidative stress (p < 0.05). In A549 cells, GCN significantly reduced PM2.5-induced reactive oxygen species (ROS) production compared with GRC (p < 0.05), with enhanced intracellular uptake confirmed using fluorescence microscopy (p < 0.05). In conclusion, GCN effectively alleviated PM2.5-induced lung damage by attenuating oxidative stress, suppressing apoptosis, and preserving the lung epithelial barrier integrity. These results emphasize its potential as a therapeutic candidate for preventing and treating the lung diseases associated with PM2.5 exposure.

Selective phosphodiesterase 4 inhibitor roflumilast reduces inflammation and lung injury in models of betacoronavirus infection in mice.

We aimed to understand the potential therapeutic and anti-inflammatory effects of the phosphodiesterase-4 (PDE4) inhibitor roflumilast in models of pulmonary infection caused by betacoronaviruses. Mice were infected intranasally with murine hepatitis virus (MHV-3) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Roflumilast was given to MHV-3-infected mice therapeutically at doses of 1mg/kg or 10mg/kg, or prophylactically at 10mg/kg. In SARS-CoV-2-infected mice, roflumilast was given therapeutically at a dose of 10mg/kg. Lung histopathology, chemokines (CXCL-1 and CCL2), cytokines (IL-1β, IL-6, TNF, IFN-γ, IL-10 and TGFβ), neutrophil immunohistochemical staining (Ly6G+ cells), macrophage immunofluorescence staining (F4/80+ cells), viral titration plaque assay, real-time PCR virus detection, and blood cell counts were examined. Therapeutic treatment with roflumilast at 10mg/kg reduced lung injury in SARS-CoV-2 or MHV-3-infected mice without compromising viral clearance. In MHV-3-infected mice, reduced lung injury was associated with decreased chemokines levels, prevention of neutrophil aggregates and reduced macrophage accumulation in the lung tissue. However, the prophylactic treatment strategy with roflumilast increased lung injury in MHV-3-infected mice. Our findings indicate that therapeutic treatment with roflumilast reduced lung injury in MHV-3 and SARS-CoV-2 lung infections. Given the protection induced by roflumilast in inflammation, PDE4 targeting could be a promising therapeutic avenue worth exploring following severe viral infections of the lung.

TRAIL agonists rescue mice from radiation-induced lung, skin or esophageal injury.

Radiotherapy can be limited by pneumonitis which is impacted by innate immunity, including pathways regulated by TRAIL death receptor DR5. We investigated whether DR5 agonists could rescue mice from toxic effects of radiation and found two different agonists, parenteral PEGylated trimeric-TRAIL (TLY012) and oral TRAIL-Inducing Compound (TIC10/ONC201) could reduce pneumonitis, alveolar-wall thickness, and oxygen desaturation. Lung protection extended to late effects of radiation including less fibrosis at 22-weeks in TLY012-rescued survivors versus un-rescued surviving irradiated-mice. Wild-type orthotopic breast tumor-bearing mice receiving 20-Gy thoracic radiation were protected from pneumonitis with disappearance of tumors. At the molecular level, radioprotection appeared due to inhibition of CCL22, a macrophage-derived chemokine previously associated with radiation pneumonitis and pulmonary fibrosis. Treatment with anti-CCL22 reduced lung injury in vivo but less so than TLY012. Pneumonitis severity was worse in female versus male mice, and this was associated with increased expression of X-linked TLR7. Irradiated mice had reduced esophagitis characterized by reduced epithelial disruption and muscularis externa thickness following treatment with ONC201 analogue ONC212. The discovery that short-term treatment with TRAIL pathway agonists effectively rescues animals from pneumonitis, dermatitis and esophagitis following high doses of thoracic radiation exposure has important translational implications.

CAVIN2 attenuates ventilator-induced lung injury in rats by MAPK/ERK1/2 signaling pathway.

Mechanical ventilation is an important treatment in medical treatment, but it may cause or aggravate lung injury, which is called ventilator-induced lung injury (VILI). Studies have shown that CAVIN2 plays an important role in regulating inflammatory responses and cell death. However, its functional mechanism in VILI remains unclear. This study explores the potential role and mechanisms of CAVIN2 in the pathogenesis of VILI. We constructed rat and cell models of VILI. Real-time quantitative polymerase chain reactions (qRT-PCR), Western blot (WB), immunohistochemistry (IHC) and immunofluorescence (IF) were used to detect CAVIN2, ERK1/2, p-ERK1/2, autophagy-associated marker proteins LC3II/I, Beclin1 and P62, and the expression level of pro-inflammatory factors IL-1β and IL-6. Hematoxylin and eosin (H&E) staining were used to evaluate the degree of pathological injury of lung tissue, and the lung permeability was evaluated by measuring the wet-dry ratio of lung tissue and the total protein content in bronchoalveolar lavage fluid (BALF). Molecular docking, co-immunoprecipitation and immunofluorescence were used to verify the binding of CAVIN2 and ERK1/2, and the regulatory mechanisms of both were investigated by rescue experiments. CAVIN2 expression was downregulated in VILI rat lung tissues and ATII cells, whereas p-ERK1/2 expression was up-regulated. Overexpressing CAVIN2 alleviated pathological damage in VILI rat lung tissues and reduced the expression of pro-inflammatory factors and autophagy-related marker proteins in both lung tissues and ATII cells. Conversely, knockdown of CAVIN2 led to increased expression of pro-inflammatory factors and autophagy-related marker proteins in ATII cells. Further mechanism studies showed that CAVIN2 binds to ERK1/2 and inhibits ERK1/2 phosphorylation. Conversely when treated with the p-ERK1/2 agonist Ro67-7476, the protective, anti-inflammatory, and anti-autophagic effects of overexpressing CAVIN2 in VILI rats and ATII cells were reversed. CAVIN2 can bind to ERK1/2 and inhibit the activation of MAPK/ERK1/2 signaling pathway to reduce inflammatory response and autophagy in VILI, thereby reducing lung injury. Therefore, CAVIN2 may be a potential intervention target to provide a new strategy for the treatment of VILI.

How can traditional Chinese medicine enhance the efficacy of antibiotics in the treatment of MRSA-infected pneumonia: An experimental study on the combination of Reyanning mixture (RYN) and linezolid.

The Reyanning Mixture (RYN) is a Chinese patent medicine widely used in the treatment of respiratory inflammatory diseases in China and has potential in the treatment of bacteria-infected pneumonia. The present study aimed to demonstrate the therapeutic potential of RYN in combination with linezolid for the treatment of MRSA-infected pneumonia and to explore the mechanisms of action and active components. The pharmacodynamics of RYN alone and in combination with linezolid was investigated in a rat model of MRSA-induced pneumonia. Transcriptomics, ELISA, Western blot and qRT-PCR were used to explore and verify the pharmacological mechanism of the anti-inflammatory effect of RYN. UPLC-MS and molecular docking were used to explore the anti-inflammatory components of RYN for the treatment of MRSA-infected pneumonia. In vivo, RYN reduced lung injury and inflammation in rats with pneumonia. In particular, the combination of RYN and linezolid enhanced the therapeutic effect compared to that of either treatment alone. Further research suggests that the synergistic therapeutic effect of the combination may be related to the inhibition of the inflammatory response by RYN and the enhancement of linezolid inhibition and clearance of MRSA in lung tissues by RYN. RYN plays an anti-inflammatory role in MRSA-infected pneumonia by inhibiting the TLR2/NF-κB/NLRP3 pathway, with 7 active components that may play a dominant role. These results indicate that RYN may serve as an adjuvant drug to antibiotics for the treatment of MRSA-associated pneumonia. Exploration of its mechanisms and active components is conducive to the clinical application and quality improvement of RYN. More importantly, this study showed that the synergistic therapeutic effect of the combination of traditional Chinese medicine and antibiotics may be a valuable therapeutic strategy.

Ginsenoside Re Alleviates Oxidative Stress Damage and Ferroptosis in Pulmonary Fibrosis Mice by Regulating the Nrf2/Keap1/GPX4 axis

Article Ginsenoside Re Alleviates Oxidative Stress Damage and Ferroptosis in Pulmonary Fibrosis Mice by Regulating the Nrf2/Keap1/GPX4 axis Huicai Lin 1,2,3, Zhaoqin Wen 1,2,3, Linying Feng 1,2,3, Xiaoyan Chen 4, Yongxiang Song 5, and Jiang Deng 1,2,3,* 1 Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi563006, China 2 Key Laboratory of Basic Pharmacology of Guizhou Province, Zunyi Medical University, Zunyi563006, China 3 The Second Affiliated Hospital of Zunyi Medical University, Zunyi Medical University, Zunyi563006, China 4 Department of Pathophysiology, Zunyi Medical University, Zunyi563006, China 5 Department of Thoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi563006, China * Correspondence: dengjiang1225@zmu.edu.cn; Tel.: +86-851-2864-3411; Fax: +86-851-2864-3411 Received: 30 August 2024; Revised: 28 September 2024; Accepted: 30 September 2024; Published: 17 December 2024 Abstract: Pulmonary fibrosis (PF) is a chronic, progressive, irreversible, fibrotic interstitial lung disease with high mortality. Ginsenoside Re (G-Re) is one of the active components of ginseng, which has been proven to possess multiple pharmacological effects, including anti-inflammatory and antioxidant. Thus, G-Re is considered a potential therapeutic agent for treating PF. The present study explored the protective mechanisms of G-Re against bleomycin (BLM)-induced PF in mice and its potential as a therapeutic strategy for PF. A mouse model of BLM-induced PF was utilized to assess the effect of G-Re treatment, with N-acetylcysteine (NAC) set as a positive control agent. Various parameters such as lung function, histopathological changes, oxidative stress markers, nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation and its related protein expressions, including Kelch-like ECH-associated protein 1 (Keap1), heme oxygenase 1 (HO-1), and NAD(P)H quinone oxidoreductase 1 (NQO-1), and ferroptosis signature protein glutathione peroxidase 4 (GPX4) were evaluated. Continuous administration of G-Re for 14 days significantly reduced lung injury, enhanced antioxidant capacity, activated the Nrf2/Keap1 signaling pathway, and inhibited ferroptosis as evidenced by GPX4. Additionally, G-Re treatment reduced collagen deposition, improved pulmonary function, and alleviated oxidative stress in the lung tissue of PF mice. These findings demonstrate that G-Re exerts its therapeutic effects against PF by modulating the Nrf2/Keap1/GPX4 axis and targeting oxidative stress and ferroptosis pathways, highlighting the potential of G-Re as a pharmacological intervention for PF and providing insights into the molecular mechanisms underlying its protective effects.

Multiomics analysis reveals signatures of selection and loci associated with complex traits in pigs

AbstractThe genetic basis of complex traits and phenotypic differentiation remains unclear in pigs. Using nine genomes—seven of which were newly generated, high‐quality de novo assembled genomes—and 1081 resequencing genomes, we built a pan‐genome and identified 134.24 Mb nonredundant nonreference sequences, 1099 novel protein‐coding genes, 187,927 structural variations (SVs) and 30,143,962 single‐nucleotide polymorphisms (SNPs). Analysis of selective domestication revealed BRCA1 associated with enhanced adipocyte growth and fat deposition, and ABCA3 linked to an alleviated immune response and reduced lung injury. Integrating 162 transcriptomes and 162 methylomes of skeletal muscle across 27 developmental stages revealed the regulatory mechanism of phenotypic differentiation between Eastern and Western breeds. Artificial selection reshaped local DNA methylation status and imparted regulatory effects on the progression patterns of heterochronic genes such as GHSR and BDH1, particularly during embryonic development. Altogether, our work provides valuable resources for understanding molecular mechanisms behind phenotypic variations and enhancing the genetic improvement programs in pigs.

Establishment of an inflammation-related acute lung injury/acute respiratory distress syndrome rat model supported by venovenous extracorporeal membrane oxygenation.

The major concerns for patients who have acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) associated with coronavirus disease 2019 or sepsis and undergone successful venovenous extracorporeal membrane oxygenation (VV ECMO) include a low survival rate and an uncontrollable inflammatory response. This study aimed to introduce an inflammation-related ALI/ARDS rat model supported by VV ECMO that is more suitable for clinical application to assess the immune response and thereby further improve survival after VV ECMO. Rats were randomly divided into three groups: the sham group, the lipopolysaccharide (LPS) group, and the LPS + ECMO group. ALI/ARDS was induced via intratracheal instillation of LPS in rats. A 5.5 F specially designed bicaval cannulation was placed in the external jugular vein for drainage and reflux. Femoral artery cannulation was used to monitor blood pressure during surgery. Arterial blood gas was measured at baseline and 3 h after VV ECMO support. Finally, lung tissue, bronchoalveolar lavage fluid (BALF) and blood samples were harvested for further evaluation. All LPS-induced ALI/ARDS rats were successfully supported by VV ECMO. The rats survived during the supporting process and maintained effective blood pressure and electrocardiogram (ECG) activity. Compared with the LPS group, VV ECMO support provided oxygen supply to restore lung function and reduced lung injury. We successfully established an inflammation-related ALI/ARDS rat model supported by VV ECMO, in which VV ECMO support alleviated lung injury. Our rat model provides a new tool for immunological research on inflammation-related ALI/ARDS during VV ECMO.

Dexmedetomidine Mitigates Acute Lung Injury by Enhancing M2 Macrophage Polarization and Inhibiting RAGE/Caspase-11-Mediated Pyroptosis.

Acute lung injury (ALI) significantly impacts the survival rates in intensive care units (ICU). Releasing a lot of pro-inflammatory mediators during the progression of the disease is a core feature of ALI, which may lead to uncontrolled inflammation and further damages the tissues and organs of patients. This study explores the potential therapeutic mechanisms of Dexmedetomidine (Dex) in ALI. In present study, cecal ligation puncture (CLP)-established ALI model mice and lipopolysaccharide (LPS)-stimulated RAW264.7 cell line were established to discover the influence of Dex. The evaluation of lung injury in vivo using histopathology, TUNEL assay, and analysis of inflammatory factors in bronchoalveolar lavage fluid (BALF) and serum. The receptor for advanced glycation end products (RAGE)/Caspase-11-dependent pyroptosis-related proteins and macrophage polarization markers were analyzed using western blot, immunofluorescence, and flow cytometry. Finally, the mechanism of Dex in macrophages was further verified in vitro. In vivo, Dex alleviated lung injury and decreased TUNEL-positive cell expression in CLP group. Dex decreased tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6 and IL-17A levels in BALF and serum, while increasing IL-10 expression. Dex treatment decreased the protein levels of RAGE, caspase-11, IL-1β and Gasdermin-D (GSDMD) in both in cells and in mice. Dex also down-regulated the synthesis of inducible nitric oxide synthase (iNOS) of classical activation phenotype (M1) markers, and up-regulated the synthesis of CD206 and Arg-1 of alternate activation phenotype (M2) markers. Dex treatment can inhibit inflammation and reduce lung injury caused by CLP. It could be associated with mediating M1 and M2 polarization and suppressing RAGE/Caspase-11-depended pyroptosis.

Moving on from clinical animal-derived surfactants to peptide-based synthetic pulmonary surfactant.

Research on lung surfactant has exerted a great impact on newborn respiratory care and significantly improved survival and outcome of preterm infants with respiratory distress syndrome (RDS) due to surfactant deficiency because of lung immaturity. Current clinical, animal-derived, surfactants are among the most widely tested compounds in neonatology However, limited availability, high production costs, and ethical concerns about using animal-derived products constitute important limitations in their universal application. Synthetic lung surfactant offers a promising alternative to animal-derived surfactant by providing improved consistency, quality and purity, availability and scalability, ease of production and lower costs, acceptance, and safety for the treatment of neonatal RDS and other lung conditions. Third-generation synthetic surfactants built around surfactant protein B (SP-B) and C (SP-C) peptide mimics stand at the forefront of innovation in neonatal pulmonary medicine, while nasal continuous positive airway pressure (nCPAP) has become the standard non-invasive respiratory support for preterm infants. nCPAP can prevent the risk of chronic lung disease (bronchopulmonary dysplasia) and reduce lung injury by avoiding intubation and mechanical ventilation, is a relatively simple technique and can be initiated safely and effectively in the delivery room. Combining nCPAP with noninvasive, preferably aerosol, delivery of synthetic lung surfactant promises to improve respiratory outcomes for preterm infants, especially in low-and-middle income countries.

"Awake" Cannulation of Patients for Venovenous Extracorporeal Membrane Oxygen: An Analysis of the Extracorporeal Life Support Organization Registry.

"Awake" cannulation for venovenous extracorporeal membrane oxygenation (ECMO), where patients remain spontaneously breathing without invasive mechanical ventilation during the cannulation procedure, may reduce lung injury from positive pressure ventilation and promote patient mobility. To examine the association between "awake" cannulation for venovenous ECMO and patient outcomes. Analysis of the prospectively collected by the multicenter Extracorporeal Life Support Organization registry. Patients 18 years old or older who were cannulated for venovenous ECMO between 2016 and 2022 were included. Propensity score matching techniques were used to examine the association between the primary exposure of "awake" cannulation and the primary outcome of hospital mortality. This study analyzed data from 28,627 patients who received venovenous ECMO, including 797 (2.8%) who underwent awake cannulation. Patients undergoing awake cannulation were older (52.2 vs. 47.8 yr), had greater prevalence of chronic lung diseases (50.6% vs. 48.9%), and ischemic heart disease (4.3% vs. 2.7%) compared with those cannulated while receiving mechanical ventilation. Hospital survival to discharge was did not differ significantly between awake and nonawake cannulation groups after propensity score matching (2.4% increased rate of survival for patients cannulated awake; 95% CI, -1.7% to 6.4%; p = 0.26). In this large, multicenter study, awake cannulation for venovenous ECMO was uncommon but increasingly used over time. Survival to hospital discharge was similar to patients cannulated while on mechanical ventilation. Future research should focus on identification of patient cohorts most likely to benefit from ""awake" cannulation.

Dexamethasone alleviates acute lung injury in a rat model with venovenous extracorporeal membrane oxygenation support

BackgroundIn recent years, dexamethasone (Dex) has been used to treat acute respiratory distress syndrome (ARDS) in patients with COVID-19 and achieved promising outcomes. Venovenous extracorporeal membrane oxygenation (VV ECMO) support...

Ciprofol prevents ferroptosis in LPS induced acute lung injury by activating the Nrf2 signaling pathway

BackgroundPatients who suffered from sepsis-induced acute lung injury (ALI) always need sedation for mechanical ventilation in intensive care unit (ICU). Ciprofol(Cip), a novel intravenous anesthetic, was revealed to have anti-inflammatory and antioxidative properties. Ferroptosis, categorized as a type of newly non-apoptotic cell death, participates in the development of lung injury. This study aimed to identify the effect of ciprofol on sepsis-induced ALI and to determine whether ferroptosis is involved.Methods and resultsTo create ALI models, MLE12 alveolar epithelial. Cells and lipopolysaccharide (LPS)-stimulated C57BL/6J mice were used. Our results displyed that Cip reduced lung injury and ferroptosis. In the LPS-induced sepsis mice model, Cip pretreatment partially reduced respiratory system damage, as evaluated by HE, TUNEL and inflammatory factors. By raising GSH levels, ciprofol activated the Nrf2 antioxidative pathway, blocked ferroptosis, increased ferroptosis-related protein (GPX4 and SLC7A11) expressions, and reduced Fe2+ content, as well as MDA and 4-HNE levels. However, the protective effects of Cip on lung injury and ferroptosis diminished in Nrf2-KO mice. Additionally, Cip activated the Nrf2 pathway and reduced cell death by preventing detrimental lipid peroxidation and ferroptosis in vitro. However, these effects were not observed in siNrf2-treated cells.ConclusionOur study demonstrated that Cip may prevent septic lung injury by suppressing ferroptosis through the Nrf2 pathway.

Disruption of the C5a/C5aR1 axis confers protection against hookworm infection in lung.

Hookworms are soil-transmitted parasitic nematodes that penetrate the host skin before migrating to the lungs. With an estimated 500-700 million people infected worldwide, hookworm infections are a neglected tropical disease and a significant cause of morbidity, particularly in children, pregnant women, and immunocompromised individuals. Although there is ample evidence that complement activation is pivotal to elicit a protective host immune response against invasive pathogens, its role in hookworm infection remains insufficiently explored. Here, we investigated the complement anaphylatoxin, C5a, during the early lung stage of infection with Nippostrongylus brasiliensis in C57BL/6J wild type and C5aR1-/- mice. Despite the previously reported ability of lung larvae to evade complement activation, C5a was detectable locally in lung tissue and bronchoalveolar lavages. Surprisingly, C5aR1 presence directly contributed to the pathogenicity of hookworm infection. The burden of viable parasites in the lungs was mitigated in C5aR1-/- mice, compared to C57BL/6J mice 48 hours post-infection. Additionally, C5aR1-/- mice showed significantly reduced lung injury, lower cytokine release, attenuated alveolar hemorrhage, and limited alveolar-capillary barrier disruption. Neutrophils were the most abundant and highest C5aR1-expressing cell type in the alveolar space after infection. Deficiency of C5aR1 reduced the influx of neutrophils, monocytes, and eosinophils to the pulmonary airways. RNA sequencing of alveolar neutrophils revealed C5aR1-dependent regulation of the novel nuclear protein, DEDD2. In conclusion, our findings highlight the impact of C5aR1 signaling in neutrophils during hookworm infection uncovering an unexpected downside of complement activation in parasitic infection.

Resolvin E1 and Inhibition of BLT2 Signaling Attenuate the Inflammatory Response and Improve One-Lung Ventilation-Induced Lung Injury

ABSTRACT Introduction One-lung ventilation (OLV) is a prevalently used technique to sustain intraoperative pulmonary function. Resolvin E1 (RvE1), a specialized pro-resolving lipid mediator, accelerates the resolution of inflammation in the lungs. However, its therapeutic effects on OLV-induced lung injury remain unclear. Methods We initially developed an OLV rat model and treated it with RvE1. Subsequently, we assessed the wet/dry ratio of the lung tissue, performed hematoxylin and eosin staining, and calculated the ratio of polymorphonuclear cells to white blood cells in the bronchoalveolar lavage fluid. Additionally, we assessed apoptosis, inflammatory factor levels, and lung permeability in the rat lung tissues in the RvE1 treated and untreated groups and explored the molecular mechanisms mediated by RvE1. Results Our results indicated that RvE1 alleviated lung injury and inflammation and improved lung tissue apoptosis and permeability in OLV rats. Moreover, RvE1 suppressed the expression of the BLT1/2 signaling pathway and its ligands. The use of BLT2 and BLT1 inhibitors (LY255283 and U-75302, respectively) enhanced RvE1’s anti-inflammatory effects and reduced lung injury. Furthermore, synergistic treatment with the BLT2 inhibitor and RvE1 provided grater benefits by more effectively inhibiting the NF-kB, p38 MAPK, and ERK pathways. Discussion RvE1 and the inhibition of BLT2 signalling reduce the inflammatory response and mitigate OLV-induced lung injury. These findings suggest a novel therapeutic pathway for managing OLV-related complications.

Pharmacological effects of koumine on acute lung injury in septic mice: From in vivo experiments and network pharmacology studies

Acute lung injury (ALI) caused by sepsis is one of the most common critical diseases, which is difficult to treat and has a high fatality rate. Koumine is one of the main active components of Gelsemium plants and has been confirmed to have potential for drug development; however, its therapeutic effects on ALI have not yet been studied. This study established ALI due to sepsis using cecal ligation and puncture (CLP) and assessed the therapeutic effects of koumine by measuring mouse survival rates, lung tissue pathological damage, inflammatory factors, and oxidative stress levels. Additionally, network pharmacology was utilized to explore the underlying mechanisms. The results showed that koumine inhibited the release of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β), thereby inhibiting inflammatory response, reducing lung injury score and lung wet to dry ratio. In addition, koumine reduced oxidative stress in mice by reducing myeloperoxidase (MPO) and malondialdehyde (MDA) and increasing superoxide dismutase (SOD) content. Network pharmacology analysis showed that 52 putative targets were relevant, and SLC6A4, HTR3A, JAK2 and JAK3 were the key targets. GO and KEGG pathway enrichment analysis showed that the related mechanisms involved neuroactive ligand-receptor interaction, calcium signaling pathway, serotonergic synapses, cholinergic synapses, etc. In summary, this study confirmed the potential therapeutic effect of koumine in sepsis induced ALI, suggesting its development prospect as a novel candidate drug for ALI, and providing data support.

Therapeutic Potential of N-acetylcysteine and Glycine in Reducing Pulmonary Injury in Diabetic Rats.

Diabetes mellitus is associated with systemic complications, including the development of pulmonary injury, characterized mainly by excessive accumulation of extracellular matrix components and inflammatory cell infiltration in lung tissue. This process is driven by oxidative stress and chronic inflammation, both caused and exacerbated by hyperglycemia. N-acetylcysteine (NAC) and glycine, known for their antioxidant and anti-inflammatory effects, offer potential therapeutic benefits in mitigating diabetes-induced lung injury. The study aimed to investigate the effects of supplementation by either NAC or glycine or their combination on reducing lung injury in rats with type 1 diabetes Materials and methods: The study used 30 adult Wistar albino rats (10 weeks old, weighing between 180 g and 380 g). Six of them were used as controls, while 24 adult rats (10 weeks old, 180-380 g) with type 1 diabetes, induced through a single intraperitoneal injection of streptozotocin (STZ) at a dose of 55 mg/kg, were randomly assigned to four experimental groups: control (CTL), diabetic (Db), NAC treatment (diabetic+NAC), glycine treatment (diabetic+glycine), and combined NAC and glycine treatment (diabetic+NAC+glycine). NAC (100 mg/kg) and glycine (250 mg/kg) were administered orally for 12 weeks. At the end of the study, lung tissues were collected for histopathological examination. Qualitative, semi-quantitative, and stereological histological analysis was used to analyze structural changes in the lung tissue. Semi-quantitative scoring was carried out to evaluate the extent of inflammation, while stereological analysis was performed to determine the volume density of alveolar spaces and septal connective tissue. The semi-quantitative scoring included scores ranging from 0 (absent), 1 (minimal), 2 (mild), 3 (moderate), to 4 (severe). Qualitative histological analysis revealed pronounced inflammation and fibrosis in the lungs of untreated diabetic rats, characterized by thickened alveolar septa and immune cell infiltration. Both treatments with NAC and glycine individually reduced inflammation and fibrosis compared to untreated diabetic rats. The greatest improvement was observed in the NAC+glycine group, where the alveolar structure appeared almost normal, with minimal inflammation. Semiquantitative analysis showed statistically significant differences in peribronchial and peribrochiolar infiltrates between the diabetic group (2.16±0.47) and the control group (0.33±0.21, p=0.026). The combination of NAC and glycine significantly reduced peribronchial and peribronchiolar infiltrates (0.33±0.33, p=0.026) compared to the diabetic group. Similarly, septal inflammatory infiltrates were significantly lower in the NAC+glycine group (1±0.36) compared to diabetic rats (3.33±0.33, p=0.004). Total airway inflammatory infiltration was also significantly reduced in the NAC+glycine group (1.33±0.33, p=0.002) compared to the diabetic group (5.5±0.5). As the combination of NAC and glycine demonstrated protective effects against lung inflammation and fibrosis in diabetic rats, a synergistic effect of NAC and glycine in mitigating pulmonary complications associated with type 1 diabetes may be suggested. These findings warrant further exploration of the combination for managing diabetic lung disease and potentially other fibrotic conditions.

Optimizing perioperative lung protection strategies for reducing postoperative respiratory complications in pediatric patients: a narrative review.

Despite significant advancements in the safe delivery of anesthesia and improvements in surgical techniques, postoperative respiratory complications (PRCs) remain a serious concern. PRCs can lead to increased length of hospital stay, worsened patient outcomes, and higher hospital and postoperative costs. Perioperative lung injury and PRCs are more common in children than in adults owing to children's unique physiology and anatomical characteristics. Studies have shown that lung-protective ventilation (LPV) strategies can improve lung function and minimize the risk of PRCs in adults. However, individualized LPV in children remains underexplored. This narrative review provides an overview of the various perioperative pulmonary protection strategies and their effect on pediatric PRCs. We searched PubMed for articles published from 2000 to 2024, setting our inclusion criteria to include studies that involved pediatric patients, addressed LPV strategies, and reported data on PRCs. Non-English language studies, case reports, editorials, conference abstracts, and non-full text published literatures were excluded. We utilized the following keyword strategy: (((lung protective ventilation) OR (PEEP)) OR (recruitment maneuver)) OR (low tidal volume) AND (2000:2024[pdat])) AND (pediatric) filters. In total, 1,106 articles were retrieved, with only 23 being deemed relevant to the review. Data extraction and analysis were conducted by two independent researchers to ensure accuracy and consistency. We conducted descriptive statistical analysis for quantitative data and thematic analysis for qualitative data. The key content are an overview of risk factors for PRCs in children including the patients themselves, anesthesia, and surgery, as well as the effectiveness of LPV strategies in pediatric surgery, including low tidal volume (TV), positive end-expiratory pressure (PEEP), ultrasound-guided pulmonary recruitment maneuver (RM), low fraction of inspired oxygen (FiO2), pressure-controlled ventilation (PCV), as well as fluids, pain, and high-flow nasal cannula (HFNC). We found that age, mechanical ventilation with general anesthesia, and thoracic surgery increased the risk of PRCs in children. The application of LPV strategies in pediatric surgery had positive effect, including low TV combined with titrated PEEP, age- and physiologically appropriate FiO2, ultrasound-guided RM, target directed fluid infusion, adequate analgesia, and the use of HFNC in special circumstances. However, we also found that the application of LPV has certain potential risks and therefore needs to be implemented according to the patient's actual age and physical condition. Perioperative LPV strategies show potential benefits in reducing lung injury and PRCs in pediatric patients. These strategies, including low TV, appropriate individualized PEEP, lung RM, and avoidance of high FiO2, appear to be effective methods for protecting lung function in pediatric patients. Additionally, perioperative fluid management and effective pain control are crucial for lung protection. The emerging use of HFNC therapy shows promise, but further research is needed to fully understand its benefits.

The protective effect of carbamazepine on acute lung injury induced by hemorrhagic shock and resuscitation in rats.

Hemorrhagic shock and resuscitation (HSR) enhances the risk of acute lung injury (ALI). This study investigated the protective effect of carbamazepine (CBZ) on HSR-induced ALI in rats. Male Sprague-Dawley rats were allocated into five distinct groups through randomization: control (SHAM), saline + HSR (HSR), CBZ + HSR (CBZ/HSR), dimethyl sulfoxide (DMSO) + HSR (DMSO/HSR), and CBZ + chloroquine (CQ) + HSR (CBZ/CQ/HSR). Subsequently, HSR models were established. To detect tissue damage, we measured lung histological changes, lung injury scores, and wet/dry weight ratios. We measured neutrophil counts as well as assessed the expression of inflammatory factors using RT-PCR to determine the inflammatory response. We detected autophagy-related proteins LC3II/LC3I, P62, Beclin-1, and Atg12-Atg5 using western blotting. Pretreatment with CBZ improved histopathological changes in the lungs and reduced lung injury scores. The CBZ pretreatment group exhibited significantly reduced lung wet/dry weight ratio, neutrophil aggregation and number, and inflammation factor (TNF-α and iNOS) expression. CBZ changed the expression levels of autophagy-related proteins (LC3II/LC3I, beclin-1, Atg12-Atg5, and P62), suggesting autophagy activation. However, after injecting CQ, an autophagy inhibitor, the beneficial effects of CBZ were reversed. Taken together, CBZ pretreatment improved HSR-induced ALI by suppressing inflammation, at least in part, through activating autophagy. Thus, our study offers a novel perspective for treating HSR-induced ALI.