Pulmonary Damage Research Articles

QiShenYiQi pills preserve endothelial barrier integrity to mitigate sepsis-induced acute lung injury by inhibiting ferroptosis

Ethnopharmacological relevanceThe QiShengYiQi pill (QSYQ) is a traditional Chinese medicinal formulation. The effectiveness and safety of QSYQ in treating respiratory system disorders have been confirmed. Its pharmacological actions include anti-inflammation, antioxidative stress, and improving energy metabolism. However, the mechanism of QSYQ in treating sepsis-induced acute lung injury (si-ALI) remains unclear. Aim of the studySi-ALI presents a clinical challenge with high incidence and mortality rates. This study aims to confirm the efficacy of QSYQ in si-ALI and to explore the potential mechanisms, providing a scientific foundation for its application and insights for optimizing treatment strategies and identifying potential active components. Materials and methodsThe impact of QSYQ on si-ALI was evaluated using the cecal ligation and puncture (CLP) experimental sepsis animal model. The effects of QSYQ on endothelial cells were observed through coculturing with LPS-stimulated macrophage-conditioned medium. Inflammatory cytokine levels, HE staining, Evans blue staining, lung wet/dry ratio, and cell count and protein content in bronchoalveolar lavage fluid were used to assess the degree of lung injury. Network pharmacology was utilized to investigate the potential mechanisms of QSYQ in treating si-ALI. Western blot and immunofluorescence analyses were used to evaluate barrier integrity and validate mechanistically relevant proteins. ResultsQSYQ reduced the inflammation and alleviated pulmonary vascular barrier damage in CLP mice (all P < 0.05). A total of 127 potential targets through which QSYQ regulates si-ALI were identified, predominantly enriched in the RAGE pathway. The results of protein-protein interaction analysis suggest that COX2, a well-established critical marker of ferroptosis, is among the key targets. In vitro and in vivo studies demonstrated that QSYQ mitigated ferroptosis and vascular barrier damage in sepsis (all P < 0.05), accompanied by a reduction in oxidative stress and the inhibition of the COX2 and RAGE (all P < 0.05). ConclusionsThis study demonstrated that QSYQ maintains pulmonary vascular barrier integrity by inhibiting ferroptosis in CLP mice. These findings partially elucidate the mechanism of QSYQ in si-ALI and further clarify the active components of QSYQ, thereby providing a scientific theoretical basis for treating si-ALI with QSYQ.

Future directions in ventilator-induced lung injury associated cognitive impairment: a new sight.

Mechanical ventilation is a widely used short-term life support technique, but an accompanying adverse consequence can be pulmonary damage which is called ventilator-induced lung injury (VILI). Mechanical ventilation can potentially affect the central nervous system and lead to long-term cognitive impairment. In recent years, many studies revealed that VILI, as a common lung injury, may be involved in the central pathogenesis of cognitive impairment by inducing hypoxia, inflammation, and changes in neural pathways. In addition, VILI has received attention in affecting the treatment of cognitive impairment and provides new insights into individualized therapy. The combination of lung protective ventilation and drug therapy can overcome the inevitable problems of poor prognosis from a new perspective. In this review, we summarized VILI and non-VILI factors as risk factors for cognitive impairment and concluded the latest mechanisms. Moreover, we retrospectively explored the role of improving VILI in cognitive impairment treatment. This work contributes to a better understanding of the pathogenesis of VILI-induced cognitive impairment and may provide future direction for the treatment and prognosis of cognitive impairment.

Department of Pharmacology of the Military Medical Academy in the 21st century: New achievements based on historical traditions (2000–2023)

In the early 2000s at the Department of Pharmacology, active research was launched into the mechanisms of hypoxia, creation of antihypoxic drugs, study of means and technologies for increasing performance, and drugs with immunomodulatory and reparative effects. The mechanisms of hypoxia and life support in extreme conditions have been a traditional area of scientific research of the department. Starting back in the 1960s under the leadership of V. M. Vinogradov, this direction gained development and scientific recognition by the end of the 1990s. During this period, new antihypoxants of direct and indirect actions were created and thoroughly studied, namely, gutimin, bemithyl, amtizol, trimetazidine, and others. Nearly all employees of the department and numerous applicants for academic degrees from among both academic and nonacademic employees participated in the research. The use of approaches and concepts of molecular physiology and pharmacology achieved very interesting and promising results for implementation. An unconditional success in scientific research in this area has been the elucidation of the molecular mechanisms of action of aminothiol-type antihypoxants, which consist in optimizing energy production and energy consumption in cells and the ability of compounds to reduce membrane damage caused by lipid peroxidation and clearly activate antioxidant systems. The second direction was the study of the molecular mechanisms of sustainable adaptation to various factors, which was started by Prof. A. V. Smirnov. Thus, long-term adaptation patterns were established in the body’s adaptation to high-altitude hypoxia, overheating, and heavy repeated loads. The contribution of individual organs to the development of these adaptive phenomena was quantitatively determined. In the experiment, effective schemes for emergency adaptation were developed using “pulse modes” of training influences against the use of pharmacological adaptogens. A significantly more pronounced adaptogenic activity has been established for drugs such as thiobenzimidazole (bemythyl) and trecrezan in comparison with known adaptogens, such as dibazole and eleutherococcus. Based on experimental data, similar schemes for pharmacologically enhanced and accelerated emergency adaptation have been developed and tested on healthy volunteers, particularly to sharp changes in climatic conditions (overheating, hypothermia, and hypoxia) and metabolic cocktails based on the antihypoxant bemityl (B-100, B-200, and B-300). These schemes and pharmacological interventions make it possible, in just a few days, to make the body noticeably adapt to the action of certain climatic factors. The third direction was the creation and study of new pharmacological agents for the correction of the effects of hypoxia, toxic pulmonary edema, and liver and immune system damage based on condensed indole systems and their product transformations. Consequently, indole derivatives (approximately 60 compounds have been synthesized and studied) are low toxic and have antihypoxic, antiedema, hepatoprotective, actoprotective and antiviral activities.

The long-lasting Ascaris suum antigens in the lungs shapes the tissue adaptation modifying the pulmonary architecture and immune response after infection in mice

Ascariasis is the most prevalent helminth affecting approximately 819 million people worldwide. The acute phase of Ascariasis is characterized by larval migration of Ascaris spp., through the intestinal wall, carried to the liver and lungs of the host by the circulatory system. Most of the larvae subsequently transverse the lung parenchyma leading to tissue injury, reaching the airways and pharynx, where they can be expectorated and swallowed back to the gastrointestinal tract, where they develop into adult worms. However, some larvae are trapped in the lung parenchyma inciting an inflammatory response that causes persistent pulmonary tissue damage long after the resolution of infection, which returns to tissue homeostasis. However, the mechanism by which chronic lung disease develops and resolves remains unknown. Here, using immunohistochemistry, we demonstrate that small fragments and larval antigens of Ascaris suum are deposited and retained chronically in the lung parenchyma of mice following a single Ascaris infection. Our results reveal that the prolonged presence of Ascaris larval antigens in the lung parenchyma contributes to the persistent immune stimulation inducing histopathological changes observed chronically following infection, and clearly demonstrate that larval antigens are related to all phases of tissue adaptation after infection: lung injury, chronic inflammation, resolution, and tissue remodeling, in parallel to increased specific humoral immunity and the recovery of lung function in mice. Additional insight is needed into the mechanisms of Ascaris antigen to induce chronic immune responses and resolution in the host lungs following larval migration.

Regulator of G protein signaling protein 6 alleviates acute lung injury by inhibiting inflammation and promoting cell self-renewal in mice

BackgroundAcute respiratory distress syndrome (ARDS) is a disease with high mortality and morbidity. Regulator of G protein signaling protein 6 (RGS6), identified as a tumor suppressor gene, has received increasing attention owing to its close relationship with oxidative stress and inflammation. However, the association between ARDS and RGS6 has not been reported.MethodsCongruously regulated G protein-coupled receptor (GPCR)-related genes and differentially expressed genes (DEGs) in an acute lung injury (ALI) model were identified, and functional enrichment analysis was conducted. In an in vivo study, the effects of RGS6 knockout were studied in a mouse model of ALI induced by lipopolysaccharide (LPS). HE staining, ELISA, and immunohistochemistry were used to evaluate pathological changes and the degree of inflammation. In vitro, qRT‒PCR, immunofluorescence staining, and western blotting were used to determine the dynamic changes in RGS6 expression in cells. The RGS6 overexpression plasmid was constructed for transfection. qRT‒PCR was used to assess proinflammatory factors transcription. Western blotting and flow cytometry were used to evaluate apoptosis and reactive oxygen species (ROS) production. Organoid culture was used to assess the stemness and self-renewal capacity of alveolar epithelial type II cells (AEC2s).ResultsA total of 110 congruously regulated genes (61 congruously upregulated and 49 congruously downregulated genes) were identified among GPCR-related genes and DEGs in the ALI model. RGS6 was downregulated in vivo and in vitro in the ALI model. RGS6 was expressed in the cytoplasm and accumulated in the nucleus after LPS stimulation. Compared with the control group, we found higher mortality, more pronounced body weight changes, more serious pulmonary edema and pathological damage, and more neutrophil infiltration in the RGS6 knockout group upon LPS stimulation in vivo. Moreover, AEC2s loss was significantly increased upon RGS6 knockout. Organoid culture assays showed slower alveolar organoid formation, fewer alveolar organoids, and impaired development of new structures after passaging upon RGS6 knockout. In addition, RGS6 overexpression decreased ROS production as well as proinflammatory factor transcription in macrophages and decreased apoptosis in epithelial cells.ConclusionsRGS6 plays a protective role in ALI not only in early inflammatory responses but also in endogenous lung stem cell regeneration.Graphical

Harnessing Endogenous Peptide Compounds as Potential Therapeutics for Severe Influenza.

Excessive pulmonary inflammation and damage are characteristic features of severe influenza virus infections. LAT8881 is a synthetic 16-amino acid cyclic peptide form of a naturally occurring C-terminal fragment of human growth hormone with therapeutic efficacy against influenza. Shorter linear peptides are typically easier to manufacture and formulate for delivery than larger cyclic peptides. A 6-amino acid linear peptide fragment of LAT8881, LAT9997, was investigated as a potential influenza therapy. LAT9997 was evaluated for its potential to limit disease in a preclinical mouse model of severe influenza infection. Intranasal treatment of mice with either LAT8881 or LAT9997 from day 1 following influenza infection significantly improved survival outcomes. Initiating LAT9997 treatment at the onset of severe disease also significantly improved disease severity. Greater disease resistance in LAT9997-treated mice correlated with reduced lung immunopathology, damage markers, vascular leak, and epithelial cell death. Treatment reduced viral loads, cytokines, and neutrophil infiltration in the airways yet maintained protective alveolar macrophages in a dose-dependent manner. Sequential trimming of N- and C-terminal amino acids from LAT9997 revealed a structure-activity relationship. These findings provide preclinical evidence that therapeutic LAT9997 treatment limits viral burden and characteristic features of severe influenza, including hyperinflammation and lung damage. Excessive pulmonary inflammation and damage are characteristic features of severe influenza virus infections. LAT9997 is a linear peptide fragment derived from human growth hormone. This study provides preclinical evidence that therapeutic LAT9997 treatment limits viral burden, hyperinflammation, and lung damage.

A Severe Case of Hantavirus Cardiopulmonary Syndrome in a Patient Presenting as STEMI

Abstract Hantavirus cardiopulmonary syndrome (HCPS) is a rare disease caused by Hantaviruses, that are transmitted from rodents to humans through aerosols. In some patients, HCPS can have a severe evolution, with rapid progression to respiratory distress and cardiogenic shock. We present the case of a 56-year-old female patient who was transferred to our hospital with ST-segment elevation myocardial infarction (STEMI) and acute respiratory distress syndrome (ARDS). The coronary angiography showed normal epicardial coronary arteries and the lung computed tomography (CT) raised the suspicion of tracheoesophageal fistula, which was soon refuted by an upper digestive endoscopy. Initially, the evolution was very severe, requiring mechanical ventilation, hemodynamic support, and broad-spectrum antibiotics. Later, sero-logical testing revealed an acute infection with Hantavirus Dobrava type. The patient lives in a rural environment, working in a wheat mill. Despite the severe presentation, the evolution was favorable, with complete remission of the pulmonary and myocardial damage after 2 weeks. We emphasize the importance of HCPS suspicion and specific testing in the early phase of the disease, as well as early admission to an intensive care unit, which is crucial in severe cases and can improve survival in a patient without any specific symptoms or a clear diagnosis.

Ultra-low tidal volume ventilation during cardiopulmonary resuscitation shows no mitigating effect on pulmonary end-organ damage compared to standard ventilation: insights from a porcine model

ObjectiveThis study aimed to determine whether ultra-low tidal volume ventilation (ULTVV) applied during cardiopulmonary resuscitation (CPR) compared with standard ventilation (intermittent positive pressure ventilation, IPPV) can reduce pulmonary end-organ damage in the post-resuscitation period.MethodsA prospective, randomized trial was conducted using a porcine model (n = 45). The animals were divided into three groups: IPPV, ULTVV, and a sham control group. Juvenile male pigs underwent CPR after inducing ventricular fibrillation and received the designated ventilation intervention [IPPV: tidal volume 6–8 ml per kilogram body weight (ml/kg BW), respiratory rate 10/min, FiO2 1.0; ULTVV: tidal volume 2–3 ml/kg BW, respiratory rate 50/min, FiO2 1.0]. A 20-h observation period followed if return of spontaneous circulation was achieved. Histopathological examination using the diffuse alveolar damage scoring system was performed on postmortem lung tissue samples. Arterial and venous blood gas analyses and ventilation/perfusion measurements via multiple inert gas elimination technique (MIGET) were repeatedly recorded during the experiment.ResultsOut of the 45 experiments conducted, 28 animals were excluded based on predefined criteria. Histopathological analysis showed no significant differences in lung damage between the ULTVV and IPPV groups. ULTVV demonstrated adequate oxygenation and decarboxylation. MIGET measurements during and after resuscitation revealed no significant differences between the intervention groups.ConclusionIn the short-term follow-up phase, ULTVV demonstrated similar histopathological changes and functional pulmonary parameters compared to standard ventilation. Further research is needed to investigate the long-term effects and clinical implications of ULTVV in resuscitation settings.

Dynamic tissue model in vitro and its application for assessment of microplastics-induced toxicity to air-blood barrier (ABB)

The replication of the hominine physiological environment was identified as an effectual strategy to develop the physiological model in vitro to perform the intuitionistic assessment of toxicity of contaminations. Herein, we proposed a dynamic interface strategy that accurately mimicked the blood flow and shear stress in human capillaries to subtly evaluate the physiological damages. To proof the concept, the dynamic air-blood barrier (ABB) model in vitro was developed by the dynamic interface strategy and was utilized to assess the toxicity of polyethylene terephthalate microplastics (PET-MPs). The developed dynamic ABB model was compared with the static ABB model developed by the conventional Transwell® system and the animal model, then the performance of the dynamic ABB model in evaluation of the PET-MPs induced pulmonary damage via replicating the hominine ABB. The experimental data revealed that the developed dynamic ABB model in vitro effectively mimicked the physiological structure and barrier functions of human ABB, in which more sophisticated physiological microenvironment enabled the distinguishment of the toxicities of PET-MPs in different sizes and different concentrations comparing with the static ABB model constructed on Transwell® systems. Furthermore, the consistent physiological and biochemical characters adopted dynamic ABB model could be achieved in a quick manner referring with that of the mouse model in the evaluation of the microplastics-induced pulmonary damage. The proposed dynamic interface strategy supplied a general approach to develop the hominine physiological environment in vitro and exhibited a potential to develop the ABB model in vitro to evaluate the hazards of inhaled airborne pollutants.

HYDROGEN PREVENTS LIPOPOLYSACCHARIDE-INDUCED PULMONARY MICROVASCULAR ENDOTHELIAL CELL INJURY BY INHIBITING STORE-OPERATED Ca 2+ ENTRY REGULATED BY STIM1/ORAI1.

Background: Sepsis is a type of life-threatening organ dysfunction that is caused by a dysregulated host response to infection. The lung is the most vulnerable target organ under septic conditions. Pulmonary microvascular endothelial cells (PMVECs) play a critical role in acute lung injury (ALI) caused by severe sepsis. The impairment of PMVECs during sepsis is a complex regulatory process involving multiple mechanisms, in which the imbalance of calcium (Ca 2+ ) homeostasis of endothelial cells is a key factor in its functional impairment. Our preliminary results indicated that hydrogen gas (H 2 ) treatment significantly alleviates lung injury in sepsis, protects PMVECs from hyperpermeability, and decreases the expression of plasma membrane stromal interaction molecule 1 (STIM1), but the underlying mechanism by which H 2 maintains Ca 2+ homeostasis in endothelial cells in septic models remains unclear. Thus, the purpose of the present study was to investigate the molecular mechanism of STIM1 and Ca 2+ release-activated Ca 2+ channel protein1 (Orai1) regulation by H 2 treatment and explore the effect of H 2 treatment on Ca 2+ homeostasis in lipopolysaccharide (LPS)-induced PMVECs and LPS-challenged mice. Methods: We observed the role of H 2 on LPS-induced ALI of mice in vivo . The lung wet/dry weight ratio, total protein in the bronchoalveolar lavage fluid, and Evans blue dye assay were used to evaluate the pulmonary endothelial barrier damage of LPS-challenged mice. The expression of STIM1 and Orai1 was also detected using epifluorescence microscopy. Moreover, we also investigated the role of H 2 -rich medium in regulating PMVECs under LPS treatment, which induced injury similar to sepsis in vitro . The expression of STIM1 and Orai1 as well as the Ca 2+ concentration in PMVECs was examined. Results:In vivo , we found that H 2 alleviated ALI of mice through decreasing lung wet/dry weight ratio, total protein in the bronchoalveolar lavage fluid and permeability of lung. In addition, H 2 also decreased the expression of STIM1 and Orai1 in pulmonary microvascular endothelium. In vitro , LPS treatment increased the expression levels of STIM1 and Orai1 in PMVECs, while H 2 reversed these changes. Furthermore, H 2 ameliorated Ca 2+ influx under sepsis-mimicking conditions. Treatment with the sarco/endoplasmic reticulum Ca 2+ adenosine triphosphatase inhibitor, thapsigargin, resulted in a significant reduction in cell viability as well as a reduction in the expression of junctional proteins, including vascular endothelial-cadherin and occludin. Treatment with the store-operated Ca 2+ entry inhibitor, YM-58483 (BTP2), increased the cell viability and expression of junctional proteins. Conclusions: The present study suggested that H 2 treatment alleviates LPS-induced PMVEC dysfunction by inhibiting store-operated Ca 2+ entry mediated by STIM1 and Orai1 in vitro and in vivo .

Effect of E. cava and C. indicum Complex Extract on Phorbol 12-Myristate 13-Acetate (PMA)-Stimulated Inflammatory Response in Human Pulmonary Epithelial Cells and Particulate Matter (PM)2.5-Induced Pulmonary Inflammation in Mice.

This study explores the potential of a natural composite formulation known as ED, consisting of Ecklonia cava (E. cava, family: Lessoniaceae) and Chrysanthemum indicum Linne (C. indicum, family: Asteraceae), in alleviating lung inflammation induced by fine particulate matter (PM2.5). Initial assessments confirmed that neither ED nor one of its components, dieckol, exhibited cytotoxic effects on A549 cells. Subsequently, the impact of ED and dieckol on MUC5AC gene expression in A549 cells stimulated by phorbol 12-myristate 13-acetate (PMA) was investigated, revealing promising results that demonstrated a dose-dependent inhibition of MUC5AC gene expression. The study also delves into the underlying mechanisms, demonstrating that ED and dieckol effectively suppressed the phosphorylation of mitogen-activated protein kinases (MAPKs), including JNK, ERK, and p38, which are known to be involved in the regulation of MUC5AC gene expression. In in vivo experiments using a PM2.5-induced pulmonary inflammation mouse model, the research findings showed that ED mitigated cellular accumulation in the airways, leading to a significant reduction in the total cell count in bronchoalveolar lavage fluid (BALF). Moreover, ED exhibited protective effects against PM2.5-induced pulmonary damage, characterized by reduced inflammatory cell infiltration and decreased mucus secretion in pulmonary tissues. Additionally, ED's anti-inflammatory properties were evident in its ability to decrease the levels of key inflammatory cytokines, TNF-α and IL-6, both in the serum and lung tissue of the PM2.5-induced pulmonary inflammation mouse model. These findings suggest the potential of ED as a therapeutic agent for inflammatory respiratory diseases.

Efficacy of RUTI® immunotherapy against active tuberculosis in a mouse model challenges the Koch phenomenon

ObjectivesThe objective of this study was to evaluate the safety and efficacy of the therapeutic vaccine RUTI® with or without the standard of care (SOC) chemotherapy for TB in an experimental murine model.MethodsWe assessed the efficacy of RUTI®, a vaccine based on pasteurized and freeze-dried cell-wall fragments from Mycobacterium tuberculosis (Mtb), the SOC for sensitive TB (isoniazid, rifampicin, ethambutol, and pyrazinamide) in the murine active TB model in C3HeB/FeJ strain (Kramnik model). We evaluated the bacillary load in the lungs and spleen, the immune response against specific Mtb antigens (PPD, HSP16.3, ESAT-6, and PsTS1), and lung damage in paraffined tissues for qualitative and quantitative analysis.ResultsRUTI® significantly reduces the pulmonary damage (x3) and the bacterial burden in the lungs (1.5 log10) and spleen (1 log10), and maintains the cellular immune response against ESAT-6, compared to SOC. There was also an additive effect when administered in combination with SOC, increasing the reduction of the lung damage (x2), the bacillary load in lungs (1 log10) and increasing the immune response against PPD, HSP16.3 and PsTS1.DiscussionTherapeutic vaccination against TB has been avoided for decades due to fear of toxicity through the Koch phenomenon. These data show for the first time the safety of immunotherapy with Mtb antigens in an active TB model, adding efficacy to SOC. This encourages the beginning of clinical studies to evaluate the safety and efficacy of RUTI® in TB patients to improve their health, reduce its potential infectiousness, and reduce the length of treatment.

Therapeutic potential of Lianhua Qingke in airway mucus hypersecretion of acute exacerbation of chronic obstructive pulmonary disease

BackgroundLianhua Qingke (LHQK) is an effective traditional Chinese medicine used for treating acute tracheobronchitis. In this study, we evaluated the effectiveness of LHQK in managing airway mucus hypersecretion in the acute exacerbation of chronic obstructive pulmonary disease (AECOPD).MethodsThe AECOPD model was established by subjecting male Wistar rats to 12 weeks of cigarette smoke (CS) exposure (80 cigarettes/day, 5 days/week for 12 weeks) and intratracheal lipopolysaccharide (LPS) exposure (200 μg, on days 1, 14, and 84). The rats were divided into six groups: control (room air exposure), model (CS + LPS exposure), LHQK (LHQK-L, LHQK-M, and LHQK-H), and a positive control group (Ambroxol). H&E staining, and AB-PAS staining were used to evaluate lung tissue pathology, inflammatory responses, and goblet cell hyperplasia. RT-qPCR, immunohistochemistry, immunofluorescence and ELISA were utilized to analyze the transcription, expression and secretion of proteins related to mucus production in vivo and in the human airway epithelial cell line NCI-H292 in vitro. To predict and screen the active ingredients of LHQK, network pharmacology analysis and NF-κB reporter system analysis were employed.ResultsLHQK treatment could ameliorate AECOPD-triggered pulmonary structure damage, inflammatory cell infiltration, and pro-inflammatory cytokine production. AB-PAS and immunofluorescence staining with CCSP and Muc5ac antibodies showed that LHQK reduced goblet cell hyperplasia, probably by inhibiting the transdifferentiation of Club cells into goblet cells. RT-qPCR and immunohistochemistry of Muc5ac and APQ5 showed that LHQK modulated mucus homeostasis by suppressing Muc5ac transcription and hypersecretion in vivo and in vitro, and maintaining the balance between Muc5ac and AQP5 expression. Network pharmacology analysis and NF-κB luciferase reporter system analysis provided insights into the active ingredients of LHQK that may help control airway mucus hypersecretion and regulate inflammation.ConclusionLHQK demonstrated therapeutic effects in AECOPD by reducing inflammation, suppressing goblet cell hyperplasia, preventing Club cell transdifferentiation, reducing Muc5ac hypersecretion, and modulating airway mucus homeostasis. These findings support the clinical use of LHQK as a potential treatment for AECOPD.

Single-cell transcriptomics reveals the pulmonary inflammation induced by inhalation of subway fine particles

People generally take the subway and inevitably inhale the fine particles (PM2.5) on subway platforms. This study revealed whether and how subway PM2.5 causes lung inflammation. Herein, the pulmonary inflammatory response to subway PM2.5 was observed in mice, manifesting as the inflammatory cells infiltration and collagen deposition in tissue, inflammatory cytokine enhancement in bronchoalveolar lavage fluid and Toll-like receptors signal pathway activation in the lungs. Furthermore, single-cell RNA sequencing unearthed subway PM2.5-induced cell-specific responses in the lungs. Twenty immune subsets were identified by the molecular and functional properties. Specific cell populations of CD4+ T and γδ T cells were regarded as the predominant sources of pneumonitis induced by subway PM2.5. Moreover, we demonstrated that the lung inflammatory injury was significantly more attenuated in Rag1−/− mice lacking functional T cells and B cells than that in wild type mice. We proved the slight inflammation of lung tissue in Rag1−/− mice may be dependent on monocytes and neutrophils by activation of the intracellular molecular network. This is the first experimental study on subway PM2.5 causing pulmonary inflammatory damage. It will set an alarm for people who usually travel by subway and efficient measures to reduce PM2.5 should be developed in subway stations.

The Effect of Moringa Leaf Extract (moringa oleifera) on the Microscopic Structure of the Lungs of Male Wistar Rats Given Inhalation of E-cigarette Liquid Vapor

Background: Moringa leaf extract is proven to have high antioxidant bioactive compounds and acts as an anti-inflammatory and prevents cell damage due to exposure to free radicals or oxidative. In the respiratory system exposed to Electronic Delivery Nicotine System liquid vapor, an inflammatory response and oxidative stress occur. Objective: This study aimed to determine the effect of Moringa leaf extract (Moringa oleifera) on the microscopic structure of the lungs of male Wistar rats given inhalation of e-cigarette liquid vapor. Methods: This research is an experimental laboratory with Post Test Only Control Group Design. Rats were divided into 4 groups containing 6 rats in each group, determined based on simple random sampling with the following divisions: Aquadest 3 mL (K1), gave inhalation of liquid vapours of electric cigarettes (K2), gave inhalation of liquid vapours of electric cigarettes + Moringa leaf extract with the dekoxy method dose of 500 mg/kgBW (P1), administration of vapor inhalation of e-cigarette liquid + Moringa leaf extract with the dekoxy method at a dose of 500 mg/kgBW (P2). Termination of the experimental animals was carried out on the 15th day and the rat pulmonary organs were taken to assess the microscopic structure of the rat lung. Results: The results of the Kruskal-Wallis test and continued with the Mann-Whitney test showed a significant difference (p &lt; 0.05), however, there was no significant difference in the degree of pulmonary damage in the P1 to P2 groups. Conclusion: There is an effect of Moringa leaf extract (Moringa oleifera) on the microscopic structure of the lungs of male Wistar rats given inhalation of liquid vapor of electric cigarettes.

Physical exercise in patients with testicular cancer treated with bleomycin, etoposide and cisplatin chemotherapy: pulmonary and vascular endothelial function—an exploratory analysis

PurposeBleomycin, etoposide, and cisplatin combination chemotherapy (BEP) improves the survival of patients with testicular cancer, but is associated with potentially life-threatening toxicities like pneumonitis and thromboembolic events. This study explored the effects of physical exercise in patients with testicular cancer during or after BEP-chemotherapy on pulmonary and vascular endothelial toxicity.MethodsIn this post hoc analysis of a multicenter randomized clinical trial (NCT01642680), patients with metastatic testicular cancer scheduled to receive BEP-chemotherapy were randomized to a 24-week exercise intervention, initiated during (group A) or after BEP-chemotherapy (group B). Endpoints were pulmonary function (forced vital capacity (FVC), forced expiratory volume in one second (FEV1), lung transfer-coefficient and transfer factor for carbon monoxide (KCO, DLCO) and markers of vascular endothelial dysfunction (von Willebrand factor (vWF) and factor VIII).ResultsThirty patients were included. Post-chemotherapy, patients declined less in FVC, FEV1 and DLCO in group A compared to group B. Post-chemotherapy, vWF and factor VIII were significantly lower in group A compared to group B. After completion of exercise, started either during BEP-chemotherapy or thereafter, no between-group differences were found. At 1-year post-intervention, significant between-group differences were found in favour of group A in DLCO and KCO.ConclusionsPatients who exercised during BEP-chemotherapy better preserved FVC, FEV1 and DLCO, measured directly post-chemotherapy and 1-year post-intervention (DLCO, KCO). This coincided with less increase in vWF and factor VIII measured directly post-chemotherapy. These data support a beneficial role of a physical exercise intervention during BEP-chemotherapy on pulmonary and vascular damage in patients with testicular cancer.Trial registryOptimal Timing of Physical Activity in Cancer Treatment (ACT) Registry URL: https://clinicaltrials.gov/ct2/show/NCT01642680. Trial registration number: NCT01642680.

Long-term impact of COVID-19 requiring elevated oxygen support and safety of prolonged positive pressure ventilation

In this study, we analyzed long-term sequelae in patients hospitalized at Montichiari Hospital (Brescia, Italy) during the COVID-19 acute phase, who needed a high-flow oxygen treatment. The follow-up evaluation has been performed after more than one year from discharge through a quality-of-life phone interview, standard laboratory tests, chest computed tomography, and global spirometry with an evaluation of the diffusing capacity of the lungs for carbon monoxide (DLCO). In our analysis, we found that patients who needed high FiO2 support during the acute phase, independently from the device used to administer it, showed a long-term heavy burden of pulmonary consequences: more than half of patients presented radiological alterations and persistent dyspnea or DLCO alterations; about 17% of them had alterations compatible with pulmonary fibrosis. Further analysis included a comparison of long-term consequences in patients treated with different devices. An interesting result was that prolonged positive pressure ventilation treatment didn’t seem to cause persistent pulmonary damage and thus could be considered a safe approach. In conclusion, this study confirms the heavy quality-of-life impact of moderate to severe COVID-19 and highlights the importance of recognizing patients who will benefit from rehabilitative programs and customized follow-up depending on the acute phase disease severity.

Adenosine Triphosphate Release From Influenza-Infected Lungs Enhances Neutrophil Activation and Promotes Disease Progression.

Adenosine triphosphate (ATP) enhances neutrophil responses, but little is known about the role of ATP in influenza infections. We used a mouse influenza model to study if ATP release is associated with neutrophil activation and disease progression. Influenza infection increased pulmonary ATP levels 5-fold and plasma ATP levels 3-fold vs healthy mice. Adding ATP at those concentrations to blood from healthy mice primed neutrophils and enhanced CD11b and CD63 expression, CD62L shedding, and reactive oxygen species production in response to formyl peptide receptor stimulation. Influenza infection also primed neutrophils in vivo, resulting in formyl peptide receptor-induced CD11b expression and CD62L shedding up to 3 times higher than that of uninfected mice. In infected mice, large numbers of neutrophils entered the lungs. These cells were significantly more activated than the peripheral neutrophils of infected mice and pulmonary neutrophils of healthy mice. Plasma ATP levels of infected mice and influenza disease progression corresponded with the numbers and activation level of their pulmonary neutrophils. Findings suggest that ATP release from the lungs of infected mice promotes influenza disease progression by priming peripheral neutrophils, which become strongly activated and cause pulmonary tissue damage after their recruitment to the lungs.

Risk of subsequent lower respiratory tract infection (LRTI) after hospitalization for COVID-19 LRTI and non-COVID-19 LRTI: a retrospective cohort study

BackgroundRespiratory pathogens, including SARS-CoV-2, can cause pulmonary structural damage and physiologic impairment, which may increase the risk of subsequent lower respiratory tract infections (LRTI). Prior hospitalization for any reason is a risk factor for LRTI, but data on the risk of subsequent new-onset LRTI following hospitalization for COVID-19 LRTI or non-COVID-19 LRTI are needed to inform strategies for immunizations targeting respiratory pathogens.MethodsWe conducted a retrospective cohort study at Kaiser Permanente Southern California (KPSC) among adults hospitalized from 3/1/2020 to 5/31/2022, excluding labor and delivery. We categorized individuals into 3 mutually exclusive baseline exposure groups: those hospitalized for COVID-19 LRTI, those hospitalized for non-COVID-19 LRTI, and those hospitalized for all other causes without LRTI or COVID-19 (“non-LRTI”). Following hospital discharge, patients were followed up for new-onset LRTI, beginning 30 antibiotic-free days after hospital discharge until 8/31/2022. We used multivariable cause-specific Cox regression with time-varying covariates to estimate hazard ratios (HR) of new-onset LRTI comparing those hospitalized for COVID-19 LRTI or non-COVID-19 LRTI to those hospitalized for non-LRTI, adjusting for demographic and clinical characteristics.ResultsThe study included 22,417 individuals hospitalized for COVID-19 LRTI, 12,795 individuals hospitalized for non-COVID-19 LRTI, and 176,788 individuals hospitalized for non-LRTI. Individuals hospitalized for non-COVID-19 LRTI were older and had more comorbidities than those hospitalized for COVID-19 LRTI or non-LRTI. Incidence rates per 1,000 person-years (95% CI) of new-onset LRTI were 52.5 (51.4–53.6) among individuals hospitalized for COVID-19 LRTI, 253.5 (243.7–263.6) among those hospitalized for non-COVID-19 LRTI, and 52.5 (51.4–53.6) among those hospitalized for non-LRTI. The adjusted hazard of new-onset LRTI during follow-up was 20% higher among individuals hospitalized for COVID-19 LRTI (HR 1.20 [95% CI: 1.12–1.28]) and 301% higher among individuals hospitalized for non-COVID-19 LRTI (HR 3.01 [95% CI: 2.87–3.15]) compared to those hospitalized for non-LRTI.ConclusionThe risk of new-onset LRTI following hospital discharge was high, particularly among those hospitalized for non-COVID-19 LRTI, but also for COVID-19 LRTI. These data suggest that immunizations targeting respiratory pathogens, including COVID-19, should be considered for adults hospitalized for LRTI prior to hospital discharge.

Markers of Local and Systemic Inflammation in the Diarrhea Syndrome Associated with the Coronavirus Disease (COVID-19)

Introduction: Fecal calprotectin is known to be a biomarker of inflammatory bowel problems. An increase in its level has been also noted in COVID-19 patients, which is associated with the pathogenic effect of the virus on the intestinal epithelium involving components of nonspecific immunity. Objective: To evaluate markers of local and systemic inflammation and their relationship in the diarrhea syndrome associated with the novel coronavirus disease (COVID-19). Materials and methods: We have analyzed medical histories of 90 laboratory-verified SARS-CoV-2 patients aged 35 to 70 years and divided them into three equal groups of 30 cases each by the measured level of fecal calprotectin (Group 1: CPT &gt; 200 μg/g, Group 2: CPT = 50 to 200 μg/g, and Group 3: CPT &lt; 50 μg/g). Results: In Group 1 patients with CPT &gt; 200 μg/g, we observed a 1.5 times more frequent severe course of the coronavirus disease, pulmonary damage over 50 % (p &lt; 0.05), fever and diarrhea that persisted up to 14.8 ± 0.5 and 8.7 ± 0.4 days, respectively (p &lt; 0.05). Conclusions: We established a direct relationship between markers of local and systemic inflammation. Clinical manifestations of COVID-19 correlated with the severity of intestinal inflammation. A positive correlation was found between fecal calprotectin levels and diarrhea syndrome duration. The landscape of opportunistic intestinal microbiota also correlated with the severity of the inflammatory process in the intestine.