Severe Lung Injury Research Articles

Hypercapnia Causes Injury of the Cerebral Cortex and Cognitive Deficits in Newborn Piglets.

In critically ill newborns, exposure to hypercapnia (HC) is common and often accepted in neonatal intensive care units to prevent severe lung injury. However, as a "safe" range of arterial partial pressure of carbon dioxide levels in neonates has not been established, the potential impact of HC on the neurodevelopmental outcomes in these newborns remains a matter of concern. Here, in a newborn Yorkshire piglet model of either sex, we show that acute exposure to HC induced persistent cortical neuronal injury, associated cognitive and learning deficits, and long-term suppression of cortical electroencephalogram frequencies. HC induced a transient energy failure in cortical neurons, a persistent dysregulation of calcium-dependent proapoptotic signaling in the cerebral cortex, and activation of the apoptotic cascade, leading to nuclear deoxyribonucleic acid fragmentation. While neither 1 h of HC nor the rapid normalization of HC was associated with changes in cortical bioenergetics, rapid resuscitation resulted in a delayed onset of synaptosomal membrane lipid peroxidation, suggesting a dissociation between energy failure and the occurrence of synaptosomal lipid peroxidation. Even short durations of HC triggered biochemical responses at the subcellular level of the cortical neurons resulting in altered cortical activity and impaired neurobehavior. The deleterious effects of HC on the developing brain should be carefully considered as crucial elements of clinical decisions in the neonatal intensive care unit.

Apolipoprotein C3 (ApoC3) facilitates NLRP3 mediated pyroptosis of macrophages through mitochondrial damage by accelerating of the interaction between SCIMP and SYK pathway in acute lung injury

Respiratory failure caused by severe acute lung injury (ALI) is the main cause of mortality in patients with COVID-19.This study aimed to investigate the effects and underlying biological mechanism of Apolipoprotein C3 (ApoC3) in ALI.To establish an in vivo model, C57BL/6 mice were exposed by lipopolysaccharide (LPS). For the in vitro model, murine bone marrow-derived macrophages (BMDMs) or RAW264.7 cells were stimulated with LPS + adenosine triphosphate (ATP).Serum levels of ApoC3 were found to be upregulated in patients with COVID-19 or pneumonia-induced ALI. Inhibition of ApoC3 reduced lung injury in an ALI model, while overexpression of ApoC3 promoted lung injury. ApoC3 induced mitochondrial damage-mediated pyroptosis in ALI through the activation of the NOD-like receptorprotein 3 (NLRP3) inflammasome. ApoC3 recombinant protein significantly increased SCIMP expression in the lung tissue of mice models with ALI. ApoC3 also facilitated the interaction between the SLP adapter and CSK-interacting membrane protein (SCIMP) protein and Spleen tyrosine kinase (SYK) protein in the ALI model. Moreover, ApoC3 accelerated calcium-dependent reactive oxygen species (ROS) production in the ALI model. The effects of ApoC3 on pyroptosis were mitigated by the use of a pyroptosis inhibitor or an ROS inhibitor in the ALI model. Furthermore, ApoC3 activated the expression of SYK, which in turn induced NLRP3 inflammasome-regulated pyroptosis in the ALI model. METTL3 was found to mediate the m6A mRNA expression of ApoC3.Overall, our study highlights the crucial role of ApoC3 in promoting macrophage pyroptosis in ALI through calcium-dependent ROS production and NLRP3 inflammasome activation via the SCIMP-SYK pathway, providing a potential therapeutic strategy for ALI and other inflammatory diseases.

METTL14 contributes to acute lung injury by stabilizing NLRP3 expression in an IGF2BP2-dependent manner

Acute lung injury (ALI) as well as its more severe form, acute respiratory distress syndrome (ARDS), frequently leads to an uncontrolled inflammatory response. N6-methyladenosine (m6A) modification was associated with the progression of several inflammatory diseases. However, the role of methyltransferase-like 14 (METTL14)-mediated m6A methylation in ALI/ARDS remains unclear. Here, we reported an increase in overall expression levels of m6A and METTL14 in circulating monocyte-derived macrophages recruited to the lung following ALI, which is correlated with the severity of lung injury. We further demonstrated the critical function of METTL14 in activating NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome in vitro and in mouse models of ALI/ARDS, and validated NLRP3 as the downstream target of METTL14 by the m6A RNA immunoprecipitation (MeRIP) and RIP assays. Mechanistically, METTL14-methylated NLRP3 transcripts were subsequently recognized by insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), an m6A reader, which stabilized NLRP3 mRNA. Furthermore, we observed that IGF2BP2 knockdown diminished LPS-induced ALI in mice by downregulating NLRP3 expression. In summation, our study revealed that the molecular mechanism underlying the pathogenesis of ALI/ARDS involves METTL14-mediated activation of NLRP3 inflammasome in an IGF2BP2 dependent manner, thereby demonstrating the potential of METTL14 and IGF2BP2 as promising biomarkers and therapeutic targets for ALI/ARDS treatment.

Hypoxia represses FOXF1 in lung endothelial cells through HIF-1α.

Introduction: Forkhead Box F1 (FOXF1) transcription factor plays a critical role in lung angiogenesis during embryonic development and lung repair after injury. FOXF1 expression is decreased in endothelial cells after lung injury; however, molecular mechanisms responsible for the FOXF1 transcript changes in injured lung endothelium remain unknown. Methods: We used immunostaining of injured mouse lung tissues, FACS-sorted lung endothelial cells from hypoxia-treated mice, and data from patients diagnosed with hypoxemic respiratory failure to demonstrate that hypoxia is associated with decreased FOXF1 expression. Endothelial cell cultures were used to induce hypoxia in vitro and identify the upstream molecular mechanism through which hypoxia inhibits FOXF1 gene expression. Results: Bleomycin-induced lung injury induced hypoxia in the mouse lung tissue which was associated with decreased Foxf1 expression. Human FOXF1 mRNA was decreased in the lungs of patients diagnosed with hypoxemic respiratory failure. Mice exposed to hypoxia exhibited reduced Foxf1 expression in the lung tissue and FACS-sorted lung endothelial cells. In vitro, hypoxia (1% of O2) or treatment with cobalt (II) chloride increased HIF-1α protein levels but inhibited FOXF1 expression in three endothelial cell lines. Overexpression of HIF-1α in cultured endothelial cells was sufficient to inhibit Foxf1 expression. siRNA-mediated depletion of HIF-1α prevented the downregulation of Foxf1 gene expression after hypoxia or cobalt (II) chloride treatment. Conclusion: Hypoxia inhibits FOXF1 expression in endothelial cells in a HIF-1α dependent manner. Our data suggest that endothelial cell-specific inhibition of HIF-1α via gene therapy can be considered to restore FOXF1 and improve lung repair in patients with severe lung injury.

Association of elastic power in mechanical ventilation with the severity of acute respiratory distress syndrome: a retrospective study

BackgroundMechanical power (MP) is the total energy released into the entire respiratory system per minute which mainly comprises three components: elastic static power, Elastic dynamic power and resistive power. However, the energy to overcome resistance to the gas flow is not the key factor in causing lung injury, but the elastic power (EP) which generates the baseline stretch of the lung fibers and overcomes respiratory system elastance may be closely related to the ARDS severity. Thus, this study aimed to investigate whether EP is superior to other ventilator variables for predicting the severity of lung injury in ARDS patients.MethodsWe retrieved patient data from the Medical Information Mart for Intensive Care III (MIMIC-III) database. The retrieved data involved adults (≥ 18 years) diagnosed with ARDS and subjected to invasive mechanical ventilation for ≥ 48 h. We employed univariate and multivariate logistic regression analyses to investigate the correlation between EP and development of moderate-severe ARDS. Furthermore, we utilized restricted cubic spline models to assess whether there is a linear association between EP and incidence of moderate-severe ARDS. In addition, we employed a stratified linear regression model and likelihood ratio test in subgroups to identify potential modifications and interactions.ResultsModerate-severe ARDS occurred in 73.4% (296/403) of the patients analyzed. EP and MP were significantly associated with moderate-severe ARDS (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.15–1.28, p < 0.001; and OR 1.15, 95%CI 1.11–1.20, p < 0.001; respectively), but EP showed a higher area-under-curve (95%CI 0.72–0.82, p < 0.001) than plateau pressure, driving pressure, and static lung compliance in predicting ARDS severity. The optimal cutoff value for EP was 14.6 J/min with a sensitivity of 75% and specificity of 66%. Quartile analysis revealed that the relationship between EP and ARDS severity remained robust and reliable in subgroup analysis.ConclusionEP is a good ventilator variable associated with ARDS severity and can be used for grading ARDS severity. Close monitoring of EP is advised in patients undergoing mechanical ventilation. Additional experimental trials are needed to investigate whether adjusting ventilator variables according to EP can yield significant improvements in clinical outcomes.

Involvement of NEK2 and NEK9 in LPS - induced endothelial barrier dysfunction

Endothelial hyperpermeability is the hallmark of severe lung injury, including acute respiratory distress syndrome. Despite the fact that Never In Mitosis A (NIMA)-related kinase 2 (NEK2) and NEK9 mediate fundamental cellular processes, our knowledge on their role in barrier function is limited. Herein we show that NEK2 and NEK9 inhibition suppresses LPS-induced paracellular hyperpermeability and myosin light chain 2 activation in endothelial cells. Moreover, the expression levels of both kinases were elevated in inflamed mouse lungs. Based on those findings, we raise the possibility that NEK2 and NEK9 may serve as novel therapeutic targets in lung inflammatory disease.

So, You Say You Want a Revolution? You Tell Me That It's Evolution: Associating Temporal Changes in Pediatric Acute Respiratory Distress Syndrome Plasma Biomarkers With Lung Injury Severity.

So, You Say You Want a Revolution? You Tell Me That It's Evolution: Associating Temporal Changes in Pediatric Acute Respiratory Distress Syndrome Plasma Biomarkers With Lung Injury Severity.

The role of soluble guanylate cyclase stimulator riociguat in preventing the development of reperfusion lung injury after balloon pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension

Aim. To evaluate the effect of prior administration of the soluble guanylate cyclase stimulator riociguat on the incidence and severity of reperfusion lung injury after balloon pulmonary angioplasty (BPA) in patients with inoperable form of chronic thromboembolic pulmonary hypertension (CTEPH).Materials and methods. 70 patients with inoperable CTEPH were included in the study. Patients were divided into 2 groups: Group 1 (n=41) – patients who had received PAH-specific therapy with riociguat at the time of BPA, Group 2 (n=29) – patients who underwent BPA without prior administration of riociguat. In the postoperative period all the patients underwent noninvasive artificial ventilation in continuous positive airway pressure mode in order to prevent the development of reperfusion damage of lungs.Results. Patients of group 1 received treatment with riocigiat for 6 months. At the time of BPA patients of both groups were matched for hemodynamic characteristics. In group 1, reperfusion edema above grade 1 occurred in 17.1% of patients, in group 2 – in 20.7% of patients, p=0.702. In group 1, manifestations of grade 3 reperfusion edema were found in 9.8% patients vs. 6.9% patients in group 2, (p=0.638). None of the patients in both groups had grade 4 or 5 reperfusion edema. Values of the index predicting the probability of reperfusion injury (PEPSI) were not significantly different in the group of patients who were pretreated with riociguat and in the group of patients who did not get PAH-specific therapy (p=0,588).Conclusion. There was no reliable evidence that administration of riociguat in recommended doses at least 6 months before BPA results in additional reduction in the incidence and severity of reperfusion pulmonary edema in patients with inoperable CTEPH.

αPD-1 immunotherapy promotes IL-17A production and promotes the formation of acute radiation-induced lung injury.

Radiotherapy (RT) is essential in the treatment of thoracic neoplasms. Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) have significantly improved the clinical management of non-small cell lung carcinoma (NSCLC). This study aimed to investigate the impact of combining anti-PD-1 (αPD-1) immunotherapy with radiotherapy on lung injury. Additionally, it investigates the role and mechanism of interleukin (IL)-17A, a pro-inflammatory cytokine involved in immune regulation, in lung injury arising from this combination treatment. Experiments were conducted using a PD-1 deficient mouse model to simulate acute radiation-induced lung injury. Inbred female BALB/c wild-type (WT) mice and PD-1-/- mice were divided into six groups: WT group, PD-1-/- group, WT_LIR + IgG group, PD-1-/-_LIR + IgG group, WT_LIR + αIL-17A group, and PD-1-/-_LIR + αIL-17A group. The mice were subjected to 8 Gy × 3 irradiation in both lungs. Various methods including histological scoring, immunofluorescence, qPCR, and flow cytometry were employed to analyze the role of IL-17A in lung injury and the effect of PD-1 gene deletion on the severity of radiation-induced lung injury. The PD-1-/-_LIR mice exhibited evident radiation-induced lung injury after receiving 8 Gy × 3 doses in both lungs. The expression level of IL-17A peaked at 2 weeks. Lung injury-related factors IFN-γ, TNF-α, IL-6, and RORγt in the PD-1-/-_LIR groups increased 2 weeks after irradiation. The CD4+ and CD8+ T cells in lung tissue of the PD-1-/-_LIR mice significantly increased. Post αIL-17A administration, the incidence of alveolitis in the treatment group decreased, the expression levels of lung injury-related factors IFN-γ, TNF-α, IL-6, RORγt, TGF-β1, and IL-17A decreased, and the CD4+ and CD8+ T cells in lung tissue significantly declined. Throughout the observation period, the survival rate of the mice in the treatment group was significantly higher than that of the isotype control group (60% vs 0%, P = 0.011). Combining αPD-1 immunotherapy with radiotherapy in mice can induce radiation-induced lung injury, with IL-17A playing a critical role in this process. αIL-17A administration significantly mitigated radiation-induced lung injury caused by the combination of αPD-1 immunotherapy and radiotherapy, improving mouse survival. This finding offers a promising treatment target for lung injury resulting from the combination of αPD-1 immunotherapy and radiotherapy.

Assessing hypoxic respiratory failure in mechanically ventilated neonates: A comparative study of oxygen saturation index and oxygenation index.

To investigate the correlation between oxygen saturation index (OSI) and oxygenation index (OI) for evaluating the blood oxygenation status in neonates with respiratory failure requiring mechanical ventilation support and to assess the predictive capability of OSI in determining clinically relevant OI cutoffs. A prospective study was conducted on neonates who received invasive mechanical ventilation at the neonatal intensive care unit of tertiary hospital in Vietnam. Bland-Altman analysis was utilized to evaluate the agreement between OSI and OI. A total of 123 neonates, including both term and preterm infants, were included in the study. A high agreement rate of 94.3% within the 95% limits of agreement (between OI and OSI), with a narrow similarity value of 3.3 (95% CI: -5.1 to 11.8) and high correlation coefficient (r = 0.791, p<0.001) was observed. The OSI cut-off value for predicting an OI of >15 was determined to be 7.45, with a sensitivity of 100% and a specificity of 87.4% (AUC 0.955; 95% CI: 0.922-0.989, p < 0.05). Similarly, an OSI cutoff value of 9.9 corresponded to an OI of 25, displaying a sensitivity of 100% and specificity of 87.4% (AUC 0.92). The receiver operating characteristic (ROC) curves for OSI exhibited statistically significant results (p < 0.05). The findings demonstrate a strong correlation between OSI and OI in neonates with respiratory failure. Furthermore, OSI, as a non-invasive method, can serve as a substitute for OI to evaluate the severity of hypoxic respiratory failure and lung injury in neonates.

Derivation of a Procedural Performance Checklist for Bifemoral Veno-Venous Extracorporeal Membrane Oxygenation Cannula Placement in Operational Environments.

Veno-venous extracorporeal membrane oxygenation (VV ECMO) is a low-frequency, high-intensity procedure used for severe lung illness or injury to facilitate rapid correction of hypoxemia and respiratory acidosis. This technology is more portable and extracorporeal support is more frequently performed outside of the hospital. Future conflicts may require prolonged causality care and more specialized critical care capabilities including VV ECMO to improve patient outcomes. We used an expert consensus survey based on a developed bifemoral VV ECMO cannulation checklist with an operational focus to establish a standard for training, validation testing, and sustainment. A 36-item procedural checklist was provided to 14 experts from multiple specialties. Using the modified Delphi method, the checklist was serially modified based on expert feedback. Three rounds of the study were performed, resulting in a final 32-item checklist. Each item on the checklist received at least 70% expert agreement on its inclusion in the final checklist. A procedural performance checklist was created for bifemoral VV ECMO using the modified Delphi method. This is an objective tool to assist procedural training and validation for medical providers performing VV ECMO in austere environments.

The effect of budesonide delivered by high-frequency oscillatory ventilation on acute inflammatory response in severe lung injury in adult rabbits.

The inflammation present in acute respiratory distress syndrome (ARDS) and thereby associated injury to the alveolar-capillary membrane and pulmonary surfactant can potentiate respiratory failure. Even considering the high mortality rate of severe ARDS, glucocorticoids appear to be a reasonable treatment option along with an appropriate route of delivery to the distal lung. This study aimed to investigate the effect of budesonide therapy delivered intratracheally by high-frequency oscillatory ventilation (HFOV) on lung function and inflammation in severe ARDS. Adult New Zealand rabbits with respiratory failure (P/F<13.3 kPa) induced by intratracheal instillation of hydrochloric acid (HCl, 3 ml/kg, pH 1.5) followed by high tidal ventilation (VT 20 ml/kg) to mimic ventilator-induced lung injury (VILI) were treated with intratracheal bolus of budesonide (0.25 mg/kg, Pulmicort) delivered by HFOV (frequency 8 Hz, MAP 1 kPa, deltaP 0.9 kPa). Saline instead of HCl without VILI with HFOV delivered air bolus instead of therapy served as healthy control. All animals were subjected to lung-protective ventilation for 4 h, and respiratory parameters were monitored regularly. Postmortem, lung injury, wet-to-dry weight ratio, leukocyte shifts, and levels of cytokines in plasma and lung were evaluated. Budesonide therapy improved the lung function (P/F ratio, oxygenation index, and compliance), decreased the cytokine levels, reduced lung edema and neutrophils influx into the lung, and improved lung architecture in interstitial congestion, hyaline membrane, and atelectasis formation compared to untreated animals. This study indicates that HFOV delivered budesonide effectively ameliorated respiratory function, and attenuated acid-induced lung injury in a rabbit model of severe ARDS.

Impact of lipopolysaccharide-induced acute lung injury in aged mice

Study Aim: As the geriatric population rapidly expands, there has been a concurrent increase in elderly admissions to intensive care units (ICUs). Acute lung injury (ALI) is a prevalent reason for these admissions and carries poorer survival rates for the aged population compared to younger counterparts. The aging lung is subject to physiological, cellular, and immunological changes. However, our understanding of how aging impacts the clinical progression of ALI is limited. This study explored the effect of aging using a murine model of ALI. Methods: Female C57BL/6J mice, aged 7–8 wk (young) and 18 months (aged), were divided into four groups: young controls, aged controls, young with ALI (YL), and aged with ALI (AL). ALI was induced via intratracheal administration of lipopolysaccharide (LPS, 0.5 mg/kg). The animals were euthanized 72 h after LPS exposure. Results: The AL group exhibited a significantly increased wet/dry ratio compared to the other three groups, including the YL group. The bronchoalveolar lavage (BAL) fluid in the AL group had more cells overall, including more neutrophils, than the other groups. Inflammatory cytokines in BAL fluid showed similar trends. Histological analyses demonstrated more severe lung injury and fibrosis in the AL group than in the other groups. Increased transcription of senescence-associated secretory phenotype markers, including PAI-1 and MUC5B, was more prominent in the AL group than in the other groups. This trend was also observed in BAL samples from humans with pneumonia. Conclusions: Aging may amplify lung damage and inflammatory responses in ALI. This suggests that physicians should exercise increased caution in the clinical management of aged patients with ALI.

Etanercept’s Protective Effect Against Lung Inflammation Caused by Polymicrobial Sepsis Induced by CLP in Male Rats

Inflammation and oxidative stress are critical factors leading to sepsis-induced severe lung injury (ALI). This study investigates the regulatory effects of Etanercept (ENT) in an animal model of sepsis-induced ALI. We established a cecal ligation and puncture (CLP) model for ALI in adult rats under anesthesia. Sepsis amplifies pathological lung tissue damage, lung endothelial permeability, serum inflammatory factor production, and the number of inflammatory cells in bronchoalveolar lavage fluid. Furthermore, it enhances the expression of phosphorylated NF-\(\kappa\)B p65, reduces lung superoxide dismutase due to CLP, and elevates lung malondialdehyde levels due to LPS-induced inflammatory factor production. This cascade of events exacerbates the expression of several genes, including TNF-\(\alpha\) and cytokines. LPS-induced inflammatory factor production also enhances the formation of reactive oxygen species in mitochondria. In summary, our current research provides evidence that ENT acts as a novel regulator of inflammation in sepsis-induced ALI in rats. The control of oxidative stress and the modulation of the inflammatory response are two key underlying mechanisms for the effects of ENT.

Post-COVID changes in lung function 6 months after veno-venous extracorporeal membrane oxygenation: a prospective observational clinical trial.

Severe coronavirus disease 2019 (COVID-19) may require veno-venous extracorporeal membrane oxygenation (V-V ECMO). While V-V ECMO is offered in severe lung injury to COVID-19, long-term respiratory follow-up in these patients is missing. Therefore, we aimed at providing comprehensive data on the long-term respiratory effects of COVID-19 requiring V-V ECMO support during the acute phase of infection. In prospective observational cohort study design, patients with severe COVID-19 receiving invasive mechanical ventilation and V-V ECMO (COVID group, n = 9) and healthy matched controls (n = 9) were evaluated 6 months after hospital discharge. Respiratory system resistance at 5 and 19 Hz (R5, R19), and the area under the reactance curve (AX5) was evaluated using oscillometry characterizing total and central airway resistances, and tissue elasticity, respectively. R5 and R19 difference (R5-R19) reflecting small airway function was also calculated. Forced expired volume in seconds (FEV1), forced expiratory vital capacity (FVC), functional residual capacity (FRC), carbon monoxide diffusion capacity (DLCO) and transfer coefficient (KCO) were measured. The COVID group had a higher AX5 and R5-R19 than the healthy matched control group. However, there was no significant difference in terms of R5 or R19. The COVID group had a lower FEV1 and FVC on spirometry than the healthy matched control group. Further, the COVID group had a lower FRC on plethysmography than the healthy matched control group. Meanwhile, the COVID group had a lower DLCO than healthy matched control group. Nevertheless, its KCO was within the normal range. Severe acute COVID-19 requiring V-V ECMO persistently impairs small airway function and reduces respiratory tissue elasticity, primarily attributed to lung restriction. These findings also suggest that even severe pulmonary pathologies of acute COVID-19 can manifest in a moderate but still persistent lung function impairment 6 months after hospital discharge. NCT05812196.

A longitudinal molecular and cellular lung atlas of lethal SARS-CoV-2 infection in K18-hACE2 transgenic mice

The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to approximately 500 million cases and 6 million deaths worldwide. Previous investigations into the pathophysiology of SARS-CoV-2 primarily focused on peripheral blood mononuclear cells from patients, lacking detailed mechanistic insights into the virus's impact on inflamed tissue. Existing animal models, such as hamster and ferret, do not faithfully replicate the severe SARS-CoV-2 infection seen in patients, underscoring the need for more relevant animal system-based research. In this study, we employed single-cell RNA sequencing (scRNA-seq) with lung tissues from K18-hACE2 transgenic (TG) mice during SARS-CoV-2 infection. This approach allowed for a comprehensive examination of the molecular and cellular responses to the virus in lung tissue. Upon SARS-CoV-2 infection, K18-hACE2 TG mice exhibited severe lung pathologies, including acute pneumonia, alveolar collapse, and immune cell infiltration. Through scRNA-seq, we identified 36 different types of cells dynamically orchestrating SARS-CoV-2-induced pathologies. Notably, SPP1+ macrophages in the myeloid compartment emerged as key drivers of severe lung inflammation and fibrosis in K18-hACE2 TG mice. Dynamic receptor-ligand interactions, involving various cell types such as immunological and bronchial cells, defined an enhanced TGFβ signaling pathway linked to delayed tissue regeneration, severe lung injury, and fibrotic processes. Our study provides a comprehensive understanding of SARS-CoV-2 pathogenesis in lung tissue, surpassing previous limitations in investigating inflamed tissues. The identified SPP1+ macrophages and the dysregulated TGFβ signaling pathway offer potential targets for therapeutic intervention. Insights from this research may contribute to the development of innovative diagnostics and therapies for COVID-19. This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2020M3A9I2109027, 2021R1A2C2004501).

Predictive factors for severe radiation-induced lung injury in patients with lung cancer and coexisting interstitial lung disease

Background and purposeThis study aimed to investigate the predictive factors of severe radiation-induced lung injury (RILI) in patients with lung cancer and coexisting interstitial lung disease (ILD) undergoing conventionally fractionated thoracic radiotherapy. Materials and methodsThe study includes consecutive patients treated with thoracic radiotherapy for lung cancer at two tertiary centers between 2010 and 2021. RILI severity was graded using the National Cancer Institute Common Terminology Criteria version 5.0, with severe RILI defined as toxicity grade ≥4, and symptomatic RILI as grade ≥2. The absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and C-reactive protein were collected within 4 weeks before starting radiotherapy. Neutrophil–lymphocyte ratios (NLR) were calculated as ANC/ALC. The median follow-up was 9 (range, 6–114) months. ResultsAmong 54 patients, 22 (40.7 %) had severe RILI. On multivariate logistic regression analysis, high pretreatment ANC (p = 0.030, OR = 4.313), pretreatment NLR (p = 0.007, OR = 5.784), and ILD severity (p = 0.027, OR = 2.416) were significant predictors of severe RILI. Dosimetric factors were not associated with severe RP. Overall survival was significantly worse for patients with severe RILI than those without, with 1-year cumulative overall survival rates of 7.4 % and 62.8 %, respectively. ConclusionPretreatment blood NLR, ANC, and ILD severity were associated with severe RILI. Overall survival was dismal for patients with severe RILI.

Histologic Characteristics and Clinical Courses of Primary Viral Pneumonia Other than COVID-19.

Objective To clarify both the histologic changes in primary viral pneumonia other than COVID-19 and whether patients with severe lung injury (SLI) on biopsy specimens progress to severe respiratory insufficiency. Methods Patients with primary viral pneumonia other than COVID-19, who underwent lung tissue biopsy, were retrospectively studied. Patients Forty-three patients (41 living patients and 2 autopsied cases) were included in the study. Results Nine patients had SLI, whereas most of patients who recovered from primary viral pneumonia showed a nonspecific epithelial injury pattern. One patient underwent a biopsy under mechanical ventilation. Two of 8 (25.0%) patients on ambient air or low-flow oxygen therapy progressed to a severe respiratory condition and then to death, while only 1 (3.1%) of 32 patients without SLI progressed to a severe respiratory condition and death (p=0.096). The proportion of patients who required O2 treatment for ≥2 weeks was higher in patients with SLI than in those without SLI (p=0.033). The 2 autopsy cases showed a typical pattern of diffuse alveolar damage, with both showing hyaline membranes. Non-specific histologic findings were present in 32 patients without SLI. Conclusion Some patients with SLI progressed to severe respiratory insufficiency, whereas those without SLI rarely progressed to severe respiratory insufficiency or death. The frequency of patients progressing to a severe respiratory condition or death did not differ significantly between those with and without SLI. The proportion of patients who required longer O2 treatment was higher in SLI group than in those without SLI.

Paralemmin-3 Augments Lipopolysaccharide-Induced Acute Lung Injury with M1 Macrophage Polarization via the Notch Signaling Pathway

BackgroundAcute lung injury (ALI) involves severe lung damage and respiratory failure, which are accompanied by alveolar macrophage (AM) activation. The aim of this article is to verify the influence of paralemmin-3 (PALM3) on alveolar macrophage (AM) polarization in ALI and the underlying mechanism of action. MethodsAn ALI rat model was established by successive lipopolysaccharide (LPS) inhalations. The influence of PALM3 on the survival rate, severity of lung injury, and macrophage polarization was analyzed. Furthermore, we explored the underlying mechanism of PALM3 in regulating macrophage polarization. ResultsPALM3 overexpression increased mortality of ALI rats, augmented lung pathological damage, and promoted AM polarization toward M1 cells. Conversely, PALM3 knockdown had the opposite effects. Mechanistically, PALM3 might promote M1 polarization by acting as an adaptor to facilitate transduction of Notch signaling. ConclusionPALM3 aggravates lung injury and induces macrophage polarization toward M1 cells by activating the Notch signaling pathway in LPS-induced ALI, which may shed light on ALI/ARDS treatments.

Long-term venovenous extracorporeal membrane oxygenation support for acute respiratory distress syndrome after COVID-19.

Acute respiratory syndrome (ARDS) following coronavirus 2 (SARS-CoV-2) infection is a serious complication often causing irreversible lung injury associated with high mortality. Extracorporeal membrane oxygenation (ECMO) may be initiated in severe cases. We present a case of ARDS following SARS-CoV-2 infection with prolonged duration ECMO (1045hours, 44days) without exchanging circuit throughout the whole duration without technical complication. A 71-year-old man of acute respiratory failure secondary to SARS-CoV-2 infection was initiated on venovenous ECMO (VV-ECMO). There was no technical complication without exchanging circuit throughout the whole prolonged ECMO duration (1045hours, 44days). Despite a great effort to improve his lung mechanics and gas exchange, there was continued clinical and physiological deterioration unfortunately. Following family discussion and with input from the multidisciplinary team (MDT) including palliative care specialists, there was recognition of deterioration despite optimal respiratory support. Shortly thereafter planned withdrawal occurred, and the patient passed away with his family at his bedside. This case study illustrates that it may be considered to use long term ECMO as a bridge to recovery or lung transplantation of ARDS patient after SARS-CoV-2 infection with severe lung injury. Benefits from proper long-term ECMO management,it is possible of sparing to exchange circuit throughout the whole prolonged duration without technical complication. This case indicates the feasibility of using of a long term VV-ECMO as a bridge to recovery or lung transplantation of ARDS patient after secondary to coronavirus 2 (SARS-CoV-2) infection with severe lung injury without circuit exchange. The optimal duration of VV-ECMO support and optimal diagnostic modalities for critical assessment of native lung recovery or irretrievable severe lung injury still require further investigation.