Circulating lactate is a critical biomarker for sepsis‐induced acute lung injury (S‐ALI) and is strongly associated with poor prognosis. However, whether elevated lactate directly promotes S‐ALI and the specific mechanism involved remain unclear. Here, this work shows that lactate causes pulmonary endothelial glycocalyx degradation and worsens ALI during sepsis. Mechanistically, lactate increases the lactylation of K18 of histone H3, which is enriched at the promoter of EGR1 and promotes its transcription, leading to upregulation of heparanase in pulmonary microvascular endothelial cells. In addition, multiple lactylation sites are identified in EGR1, and lactylation is confirmed to occur mainly at K364. K364 lactylation of EGR1 facilitates its interaction with importin‐α, in turn promoting its nuclear localization. Importantly, this work identifies KAT2B as a novel lactyltransferase whose GNAT domain directly mediates the lactylation of EGR1 during S‐ALI. In vivo, suppression of lactate production or genetic knockout of EGR1 mitigated glycocalyx degradation and ALI and improved survival outcomes in mice with polymicrobial sepsis. Therefore, this study reveals that the crosstalk between metabolic reprogramming in endothelial cells and epigenetic modifications plays a critical role in the pathological processes of S‐ALI.

Background. To investigate the association between interleukins (IL‐1β, IL‐2, IL‐4, IL‐6, IL‐8, and IL‐10) and the disease severity of coronavirus disease 2019 (COVID‐19). Materials and Methods. We systematically searched records investigating the role of interleukins (IL‐1β, IL‐2, IL‐4, IL‐6, IL‐8, and IL‐10) in COVID‐19 patients in Web of Science, Pubmed, and Embase through December 2020. Data were extracted and pooled, and the weighted mean difference (WMD) and its 95% confidence interval (CI) were calculated. The funnel plot and the nonparametric trim and fill method were used to visualize and adjust the publication bias. Results. In total, 61 studies enrolled 14,136 subjects (14,041 patients and 95 healthy subjects) were enrolled in this meta‐analysis. Our results showed that serum IL‐2, IL‐4, IL‐6, and IL‐10 levels were elevated in COVID‐19 patients compared to healthy controls, and IL‐6, IL‐8, and IL‐10 levels were increased in severe COVID‐19 cases compared to nonsevere patients. Additionally, the levels of IL‐1β, IL‐6, and IL‐8 were elevated in nonsurvivor patients compared to survivors. For patients in the intensive care unit (ICU), IL‐6 and IL‐8 levels were increased than that in non‐ICU patients. Conclusions. Elevated levels of IL‐6, IL‐8, and IL‐10 were associated with the disease severity of COVID‐19, and elevated levels of IL‐1β, IL‐6, and IL‐8 were related to the prognosis of COVID‐19 patients, which could be used to evaluate COVID‐19 patients’ disease severity and prognosis.

Background: Circulating lactate is associated with poor prognosis in sepsis-induced acute lung injury (S-ALI). However, it remains unclear whether microvascular dysfunction, a hallmark of S-ALI, is related to circulating lactate levels and what the underlying mechanisms are. The aim of this study was to investigate the role and mechanisms of lactate in pulmonary microvascular dysfunction in S-ALI. Methods: The effects of lactate on pulmonary microvascular function were assessed in a septic mouse model. Primary mouse pulmonary microvascular endothelial cells (MPMVECs) were isolated to evaluate the impact of lactate on MPMVEC permeability. Transcriptomic sequencing was employed to investigate the involvement of lactate in regulating MPMVEC ferroptosis, and the results were validated by in vivo and in vitro experiments. Histone lactylation was identified as a regulator of lipid peroxidation and iron homeostasis dysregulation in lactate-induced ferroptosis in MPMVECs. Gain- and loss-of-function approaches were used to assess the role of histone lactylation in regulating ferroptosis and pulmonary microvascular dysfunction. Correlations between serum lactate and ferroptosis levels and their associations with patient prognosis were investigated in patients with sepsis-associated acute respiratory distress syndrome (S-ARDS). Results: The mouse serum lactate level reached a peak at 18 h after caecal ligation and puncture surgery. Elevated lactate levels during sepsis promoted ferroptosis in PMVECs, leading to increased pulmonary vascular permeability and exacerbation of ALI. Mechanistically, lactate increased the lactylation of histone H3 at K18 (H3K18la), which promoted ACSL4 transcription in MPMVECs, resulting in excessive lipid peroxidation. Additionally, elevated H3K18la promoted LC3 transcription and indirectly upregulated NCOA4 expression through the transcription factor GATA2, facilitating ferritinophagy. Serum lactate levels were significantly correlated with ferroptosis levels in S-ARDS patients, and both were associated with poor patient prognosis. Conclusions: This study revealed a critical role for high lactate-derived histone lactylation in PMVEC ferroptosis and the progression of ALI during sepsis, providing new insights and potential therapeutic mechanisms.

Introduction Stenotrophomonas maltophilia is an opportunistic pathogen associated with various nosocomial infections and is known for its intrinsic multidrug resistance. This study aims to provide a comprehensive overview of the epidemiology and resistance patterns of S. maltophilia in China from 2014 to 2021. Methods Data were extracted from the China Antimicrobial Resistance Surveillance System (CARSS) and the Blood Bacterial Resistance Investigation Collaborative System (BRICS), encompassing 1412 medical institutions across 31 provinces in China. We analyzed the prevalence of S. maltophilia in clinical isolates, focusing on specific patient populations and departments, as well as resistance profiles to recommended first-line antibiotics, including sulfamethoxazole-trimethoprim, levofloxacin, and minocycline. Results A total of 514,768 S. maltophilia strains were analyzed. The overall prevalence of S. maltophilia among all clinical bacterial isolates remained stable at approximately 2.1%, with higher rates observed in intensive care units and elderly patients. Resistance rates to sulfamethoxazole-trimethoprim decreased from 9.8% in 2014 to 7.5% in 2021. In contrast, resistance to levofloxacin showed a slight upward trend, increasing from 8.5% in 2014 to 9.5% in 2021. Meanwhile, minocycline resistance remained low, fluctuating marginally from 2.7% in 2014 to 1.7% in 2021. Conclusions This study highlights the stable prevalence of S. maltophilia in clinical settings in China and the overall low resistance rates to recommended first-line antibiotics. However, alarmingly high resistance rates were observed in specific specimen types, particularly in blood cultures, suggesting that minocycline may be the only reliable therapeutic option among the six tested antibiotics for treating such infections in China. Continuous surveillance and effective infection control measures are essential to manage S. maltophilia infections, particularly in vulnerable populations. Future research should focus on measuring the true burden of these infections and monitoring the susceptibility of the newly introduced antibiotics, such as cefiderocol.

Introduction: Acute lung injury (ALI) and its most severe form acute respiratory distress syndrome (ARDS) are commonly occurring devastating conditions that seriously threaten the respiratory system in critically ill patients. The current treatments improve oxygenation in patients with ALI/ARDS in the short term, but do not relieve the clinical mortality of patients with ARDS. Purpose: To develop the novel drug delivery systems that can enhance the therapeutic efficacy of ALI/ARDS and impede adverse effects of drugs. Methods: Based on the key pathophysiological process of ARDS that is the disruption of the pulmonary endothelial barrier, bilirubin (Br) and atorvastatin (As) were encapsulated into an intelligent reactive oxygen species (ROS)-responsive nanocarrier DSPE-TK-PEG (DPTP) to form nanoparticles (BA@DPTP) in which the thioketal bonds could be triggered by high ROS levels in the ALI tissues. Results: BA@DPTP could accumulate in inflammatory pulmonary sites through passive targeting strategy and intelligently release Br and As only in the inflammatory tissue via ROS-responsive bond, thereby enhancing the drugs effectiveness and markedly reducing side effects. BA@DPTP effectively inhibited NF-κB signaling and NLRP3/caspase-1/GSDMD-dependent pyroptosis in mouse pulmonary microvascular endothelial cells. BA@DPTP not only protected mice with lipopolysaccharide-induced ALI and retained the integrity of the pulmonary structure, but also reduced ALI-related mortality. Conclusion: This study combined existing drugs with nano-targeting strategies to develop a novel drug-targeting platform for the efficient treatment of ALI/ARDS.