Lung Apoptosis Research Articles

The protective and antiapoptotic effects of Hypericum triquetrifolium Turra against cyclophosphamide-induced lung injury in rats: in vitro evaluation

Objectives: Hypericum triquetrifolium Turra (HTT) has been traditionally used in medical treatments due to its sedative, antiseptic, antiinflammatory, and anthelmintic properties. The present study aims to investigate the lung-protective and antiapoptotic effects of HTT against cyclophosphamide (CP)-induced lung injury in rats. Methods: Thirty-five Sprague Dawley rats were categorized into 5 groups, each consisting of seven members. Phenolic acid and flavonoid contents of this plant were determined. The lung tissue samples cultivated from the rats were examined in histopathological and immunohistochemically for the apoptosis markers of Caspase-3, Bax, and Bcl-2. Results: Histopathological results indicated that structural defects, bleeding areas, and edema had occurred in the lungs of the CP-Alone Group. Besides, Caspase-3 and Bax positivity of the lung cells had also increased while Bcl-2 positivity had decreased. On the other hand, in the HTT+CP Group, HTT was shown to have reversed the aforementioned changes positively. Conclusion: Based on in vivo results, HTT could be a strong protective candidate for CP-induced lung injury and apoptosis

Role of ATF3 triggering M2 macrophage polarization to protect against the inflammatory injury of sepsis through ILF3/NEAT1 axis

BackgroundSepsis is a systemic inflammatory response which is frequently associated with acute lung injury (ALI). Activating transcription factor 3 (ATF3) promotes M2 polarization, however, the biological effects of ATF3 on macrophage polarization in sepsis remain undefined.MethodsLPS-stimulated macrophages and a mouse model of cecal ligation and puncture (CLP)-induced sepsis were generated as in vitro and in vivo models, respectively. qRT-PCR and western blot were used to detect the expression of ATF3, ILF3, NEAT1 and other markers. The phenotypes of macrophages were monitored by flow cytometry, and cytokine secretion was measured by ELISA assay. The association between ILF3 and NEAT1 was validated by RIP and RNA pull-down assays. RNA stability assay was employed to assess NEAT1 stability. Bioinformatic analysis, luciferase reporter and ChIP assays were used to study the interaction between ATF3 and ILF3 promoter. Histological changes of lung tissues were assessed by H&E and IHC analysis. Apoptosis in lungs was monitored by TUNEL assay.ResultsATF3 was downregulated, but ILF3 and NEAT1 were upregulated in PBMCs of septic patients, as well as in LPS-stimulated RAW264.7 cells. Overexpression of ATF3 or silencing of ILF3 promoted M2 polarization of RAW264.7 cells via regulating NEAT1. Mechanistically, ILF3 was required for the stabilization of NEAT1 through direct interaction, and ATF3 was a transcriptional repressor of ILF3. ATF3 facilitated M2 polarization in LPS-stimulated macrophages and CLP-induced septic lung injury via ILF3/NEAT1 axis.ConclusionATF3 triggers M2 macrophage polarization to protect against the inflammatory injury of sepsis through ILF3/NEAT1 axis.

Urolithin A exerts a protective effect on lipopolysaccharide-induced acute lung injury by regulating HMGB1-mediated MAPK and NF-κB signaling pathways.

Acute lung injury (ALI) is a severe inflammatory disorder that has a high morbidity and mortality rate. Urolithin A (UA) is reported to have anti-inflammatory and anti-oxidative effects in ALI. However, its molecular mechanisms in ALI remain to be explored. Mice and BEAS-2B cells were administrated with lipopolysaccharide (LPS) to mimic the ALI model in vivo and in vitro. Hematoxylin-eosin (HE) staining was used to detect the pathological injury of lung tissues. The levels of proinflammatory cytokines in bronchoalveolar lavage fluid (BALF) and culture supernatant and the levels of oxidative stress markers in lung tissues were measured using ELISA. DCFH-DA probe was used to assess the reactive oxygen species (ROS) level. TUNEL staining and flow cytometry were performed to determine cell apoptosis. The key targets and pathways were confirmed by immunohistochemistry (IHC) and western blot. UA suppressed the pathologic damage, wet/dry weight ratio, and total protein and inflammatory cells in BALF. UA decreased neutrophil infiltration and proinflammatory cytokines production. UA reduced the level of malondialdehyde (MDA) and increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in pulmonary tissues. UA also inhibited cell apoptosis in lung tissues by decreasing Bax expression and increasing Bcl-2 expression. In addition, UA suppressed LPS-induced inflammatory factor production, ROS level, and cell apoptosis in BEAS-2B. Importantly, UA decreased the expression of HMGB1 in LPS-treated mice and BEAS-2B cells. HMGB1 overexpression greatly abrogated the inhibition of UA on inflammation, ROS, and cell apoptosis in LPS-administrated BEAS-2B. Furthermore, UA treatment suppressed the phosphorylated levels of p38, JNK, ERK, and p65 in LPS-administrated mice and BEAS-2B cells. UA alleviated lung inflammation, oxidative stress, and apoptosis in ALI by targeting HMGB1 to inactivate the MAPK/NF-κB signaling, suggesting the potential of UA to treat ALI.

Adverse effects of cigarette filter silica on lungs: Comparison with natural crystalline silica particles.

As a common additive in cigarette filters, nanosilica has been implemented to reduce the release of harmful substances in cigarette smoke. However, the potential risk of occupational exposure for cigarette factory workers is unknown. We collected physical examination data from 710 cigarette factory workers to evaluate the adverse effects of cigarette filter silica exposure. We also established mouse models induced by cigarette filter silica and crystalline silica separately to compare the lung inflammation, pulmonary function, apoptosis, and fibrosis of the two models. Workers in the rolling and packing workshop exposed to cigarette filter silica had a higher rate of abnormal lung function (17.75%) than those in the cutting workshop (0.87%). Animal experiments showed that compared with the same dose of crystalline silica, cigarette filter silica resulted in higher levels of inflammatory factors in the bronchoalveolar lavage fluid (BALF) of mice at day 7, and lower levels of total lung capacity (TLC), inspiratory capacity (IC), vital capacity (VC), and forced vital capacity (FVC) in mice at day 28. Additionally, both exposed groups of mice showed increased levels of caspase 3, collagen I (Col-Ⅰ), α-smooth muscle actin (α-SMA) and hydroxyproline (HYP) in the lungs, as well as collagen accumulation and fibrous nodules at day 28, with no significant difference between the two groups. The results suggested that cigarette filter silica caused more severe early lung inflammation and late ventilation impairment than the same dose of crystalline silica. In the future, we need to pay more attention to nanosilica protection in cigarette factories to prevent pulmonary dysfunction in workers.

Biological Properties of Extracts Obtained from In Vitro Culture of Plectranthus scutellarioides in a Cell Model.

Plectranthus scutellarioides (L.) R.Br. is a medicinal plant that has long been used in traditional medicine to treat conditions such as abscesses, ulcers, and ear and eye infections. It is known to have a wide range of biological properties, such as antibacterial, antioxidant, antifungal, anti-inflammatory, anti-diabetic and anti-cancer effects. In this study, we established in vitro cultures from both the aerial parts and roots of Plectranthus scutellarioides. Subsequently, we compared the basic phytochemical profile of the obtained extracts and conducted a biological analysis to assess their potential for inducing apoptosis in breast (MCF-7) and lung (A549) cancer cells. Phytochemical analysis by HPLC-MS revealed the presence of compounds belonging to phenolic acids (ferulic, syringic, vanillic, rosmarinic, chlorogenic, caffeic, coumaric, dihydroxybenzoic acids), flavonoids (eriodyctiol and cirsimaritin), and terpenes such as 6,11,12,14,16-Pentahydroxy-3,17diacetyl-8,11,13-abietatrien-7-one, 6,11,12,14,16-Pentahydroxy-3,17-diacetyl5,8,11,13-abietatetraen-7-one, and 3,6,12-Trihydroxy-2-acetyl-8,12-abietadien7,11,14-trione. The results show that both extracts have a cytotoxic and genotoxic effect against MCF-7 and A549 cancer cells, with a different degree of sensitivity. It was also shown that both extracts can induce apoptosis by altering the expression of apoptotic genes (Bax, Bcl-2, TP53, Fas, and TNFSF10), reducing mitochondrial membrane potential, increasing ROS levels, and increasing DNA damage. In addition, it has been shown that the tested extracts can alter blood coagulation parameters. Our results indicate that extracts from in vitro cultures of Plectranthus scutellarioides aerial parts and roots have promising therapeutic application, but further research is needed to better understand the mechanisms of their action in the in vitro model.

A NOVEL OLIGONUCLEOTIDE MRNA MIMIC ATTENUATES HEMORRHAGE-INDUCED ACUTE LUNG INJURY.

Hemorrhagic shock (HS) is accompanied by a pronounced activation of the inflammatory response in which acute lung injury (ALI) is one of the most frequent consequences. Among the pivotal orchestrators of this inflammatory cascade, extracellular cold-inducible RNA-binding protein (eCIRP) emerges as a noteworthy focal point, rendering it as a promising target for the management of inflammation and tissue injury. Recently, we have reported that oligonucleotide poly(A) mRNA mimic termed A 12 selectively binds to the RNA binding region of eCIRP and inhibits eCIRP binding to its receptor TLR4. Furthermore, in vivo administration of eCIRP induces lung injury in healthy mice and that mouse deficient in CIRP showed protection from inflammation-associated lung injury. We hypothesize that A 12 inhibits systemic inflammation and ALI in HS. To test the impacts of A 12 on systemic and lung inflammation, extent of inflammatory cellular infiltration and resultant lung damage were evaluated in a mouse model of HS. Male mice were subjected to controlled hemorrhage with a mean arterial pressure of 30 mm Hg for 90 min and then resuscitated with Ringer's lactate solution containing phosphate-buffered saline (vehicle) or A 12 at a dose of 4 nmol/g body weight (treatment). The infusion volume was twice that of the shed blood. At 4 h after resuscitation, mice were euthanized, and blood and lung tissues were harvested. Blood and tissue markers of inflammation and injury were evaluated. Serum markers of injury (lactate dehydrogenase, alanine transaminase, and blood urea nitrogen) and inflammation (TNF-α, IL-6) were increased after HS and A 12 treatment significantly decreased their levels. A 12 treatment also decreased lung levels of TNF-α, MIP-2, and KC mRNA expressions. Lung histological injury score, neutrophil infiltration (Ly6G staining and myeloperoxidase activity), and lung apoptosis were significantly attenuated after A 12 treatment. Our study suggests that the capacity of A 12 in attenuating HS-induced ALI and may provide novel perspectives in developing efficacious pharmaceutics for improving hemorrhage prognosis.

Programmed cell death 4 governs NLRP3-mediated pyroptosis in septic lung disorders.

Sepsis is a pathogenic syndrome of prolonged excessive inflammation and immunosuppression produced by invading pathogens. Programmed cell death 4 (PDCD4) may be implicated in a range of inflammatory lesions, and this study aimed to confirm the involvement of PDCD4 in septic lung injury. Mice and bronchial epithelial 16HBE cells were separately subjected to CLP and LPS to generate in vivo and in vitro models. Following the level of PDCD4 was determined, the impacts of PDCD4 knockdown on mouse lung injury degree, inflammation, apoptosis, and pyroptosis levels were evaluated. Afterward, cells were treated with the NLRP3 agonist, and the influences of NLRP3 activation on the regulations of PDCD4 knockdown were determined. PDCD4 was elevated following mice developed septic lung injury, PDCD4 knockdown ameliorated septic lung injury and reduced lung inflammation and apoptosis. Moreover, PDCD4 knockdown suppressed NLRP3-mediated pyroptosis, indicating that PDCD4 also mediated pyroptosis. According to cellular models, NLRP3 activation broke the effects of PDCD4 knockdown on cells. The current study reveals that PDCD4 governs NLRP3-mediated pyroptosis in septic lung injury. PDCD4 is not only related to apoptosis and expands the knowledge of PDCD4 regulation of different cell death modes.

Green tea polyphenols inhibit TBBPA-induced lung injury via enhancing antioxidant capacity and modulating the NF-κB pathway in mice.

Tetrabromobisphenol A (TBBPA) is a global pollutant. When TBBPA is absorbed by the body through various routes, it can have a wide range of harmful effects on the body. Green tea polyphenols (GTPs) can act as antioxidants, resisting the toxic effects of TBBPA on animals. The effects and mechanisms of GTP and TBBPA on oxidative stress, inflammation and apoptosis in the mouse lung are unknown. Therefore, we established in vivo and in vitro models of TBBPA exposure and GTP antagonism using C57 mice and A549 cells and examined the expression of factors related to oxidative stress, autophagy, inflammation and apoptosis. The results of the study showed that the increase in reactive oxygen species (ROS) levels after TBBPA exposure decreased the expression of autophagy-related factors Beclin1, LC3-II, ATG3, ATG5, ATG7 and ATG12 and increased the expression of p62; oxidative stress inhibits autophagy levels. The increased expression of the pro-inflammatory factors IL-1β, IL-6 and TNF-α decreased the expression of the anti-inflammatory factor IL-10 and activation of the NF-κB p65/TNF-α pathway. The increased expression of Bax, caspase-3, caspase-7 and caspase-9 and the decreased expression of Bcl-2 activate apoptosis-related pathways. The addition of GTP attenuated oxidative stress levels, restored autophagy inhibition and reduced the inflammation and apoptosis levels. Our results suggest that GTP can attenuate the toxic effects of TBBPA by modulating ROS, reducing oxidative stress levels, increasing autophagy and attenuating inflammation and apoptosis in mouse lung and A549 cells. These results provide fundamental information for exploring the antioxidant mechanism of GTP and further for studying the toxic effects of TBBPA.

Fabrication of facile assembly shrinkable double-responsive nanoparticles: Investigation of anticancer activity in lung cancer cells and apoptosis induction

Nanoparticle-based delivery techniques have low stability, poor tumour penetration, and uncontrolled drug release. To address these issues, the present study designed HAD (the compound of Halloysite (HS), alginate oligosaccharides (AOS), and doxorubicin (DOX)). This shrinkable nanoparticle responds to changes in pH and enzyme activity in the tumour microenvironment. DOX, an anticancer drug in HAD, is durable in serum-comprising water solutions and readily accumulates in tumours in vitro, despite its small size (100 nm). Because of the abundance of lysozymes in the tumour extracellular matrix, HAD can be reduced from 100 nm to 30 nm (in size), allowing the drug to enter the tumour tissue more easily. In addition, once internalised by tumour cells, the DOX is rapidly released, and the acidic and enzymatic cellular microenvironment quickly kills the cancer cells. An excellent reduction in the A549 cells' dose-dependent viability observed the HAD's cytotoxic potential. The enhanced reactive oxygen species (ROS) accumulations and reduction of MMP were perceived in the HAD-treated cells. The improved caspase-3, − 9, and − 8 expressions were also seen in the HAD-exposed A549 cells. These findings show that HAD has been promised as a beneficial delivery method for cancer treatment since it can assure a regulated drug release specifically targeted to lung tumour cells.

Aflatoxin B1 administration causes inflammation and apoptosis in the lungs and spleen

Aflatoxin is a naturally occurring mycotoxin that has numerous toxic effects. The main aim of the present study was to evaluate the toxic effects of aflatoxin B1 (AFB1) on the lungs and spleen. Mice were repeatedly exposed to AFB1 (0.3 mg/kg body weight) on alternate days for four weeks via oral route. The histopathological data in AFB1-treated mice show alveolar epithelial hyperplasia with inflammation and the presence of numerous alveolar macrophages with minimal hemorrhage. There was an increase in vascular neutrophils and interstitial inflammation. The branching of vessels was plugged with neutrophils. AFB1 administration also causes splenomegaly. The AFB1-treated spleen shows the tingible body macrophages (TBM) scattered within the splenic white pulp. Apoptosis may lead to atrophy in a selected region of the white pulp area. There is a decrease in cellularity within the periarteriolar lymphatic sheath (PALS). The inflammation causes the congestion of red pulp with the increase in nuclear debris, and vacuoles are also visible. The flow cytometry data further suggests enhanced apoptosis in lung and spleen cells.

Ninety Sixth-Hour Impact of Scalding Burns on End Organ Damage, Systemic Oxidative Stress, and Wound Healing in Rats Treated With Three Different Types of Dressings.

In this study, we investigated the effects of 3 different burn dressing treatments, including experimental, silver, and modern dressing materials, on systemic oxidative stress in rats with severe scald burns within the first 96 h. The rats were divided into five groups: a burn group (n = 10), a polylactic membrane group (n = 10), a silver sulfadiazine group (n = 10), a curcumin group (n = 10), and a control group (n = 10), consisting of equal numbers of female and male rats. In the first 4 groups, 30% of the rats' total body surface area was scalded at 95°C. The burn group was not treated. Each group was treated with group-name dressing material. The control group was neither treated nor burned. The rats were sacrificed, and blood and tissue samples were obtained at the 96th hour when severe effects of oxidative stress developed postburns. Systemic inflammatory biomarkers and oxidative stress parameters were examined. In addition, apoptosis and organ damage in liver, kidney, lung, and skin tissues were evaluated biochemically and histopathologically. When the parameters were statistically analyzed, we found that the systemic levels of oxidative stress and inflammatory damage to liver, kidney, and lung tissues were lower in the 3 treated groups than in the burn group. We believe that the dressing material's efficacy in the treatment of severe burns may be dependent on its ability to combat oxidative stress and inflammation.

Polystyrene nanoplastics-induced lung apoptosis and ferroptosis via ROS-dependent endoplasmic reticulum stress

It has been shown that exposure to nanoplastics (MNPs) through inhalation can induce pulmonary toxicity, but the toxicological mechanism of MNPs on the respiratory system remains unclear. Therefore, we explored the toxicological mechanism of exposure to polystyrene nanoplastics (PS-NPs) (0.05, 0.15, 0.2 mg/mL) on BEAS-2B cells. Results revealed that PS-NPs induce oxidative stress, increased apoptosis rate measured by flow cytometry, the key ferroptosis protein (GPX4 and FTH1) reduction, increased iron content, mitochondrial alterations, and increased malondialdehyde (MDA) level. Besides, consistent results were observed in mice exposed to PS-NPs (5 mg/kg/2d, 10 mg/kg/2d). Thus, we proved that PS-NPs induced cell death and lung damage through apoptosis and ferroptosis. In terms of mechanism, the elevation of the endoplasmic reticulum (ER) stress protein expression (IRE1α, PERK, XBP1S, and CHOP) revealed that PS-NPs induce lung damage by activating the two main ER stress pathways. Furthermore, the toxicological effects of PS-NPs observed in this study are attenuated by the ROS inhibitor N-acetylcysteine (NAC). Collectively, NPs-induced apoptosis and ferroptosis are attenuated by NAC via inhibiting the ROS-dependent ER stress in vitro and in vivo. This improves our understanding of the mechanism by which PS-NPs exposure leads to pulmonary injury and the potential protective effects of NAC.

Vitamin E stabilizes iron and mitochondrial metabolism in pulmonary fibrosis.

Introduction: Pulmonary fibrosis (PF) is a fatal chronic lung disease that causes structural damage and decreased lung function and has a poor prognosis. Currently, there is no medicine that can truly cure PF. Vitamin E (VE) is a group of natural antioxidants with anticancer and antimutagenic properties. There have been a few reports about the attenuation of PF by VE in experimental animals, but the molecular mechanisms are not fully understood. Methods: Bleomycin-induced PF (BLM-PF) mouse model, and cultured mouse primary lung fibroblasts and MLE 12 cells were utilized. Pathological examination of lung sections, immunoblotting, immunofluorescent staining, and real-time PCR were conducted in this study. Results: We confirmed that VE significantly delayed the progression of BLM-PF and increased the survival rates of experimental mice with PF. VE suppressed the pathological activation and fibrotic differentiation of lung fibroblasts and epithelial-mesenchymal transition and alleviated the inflammatory response in BLM-induced fibrotic lungs and pulmonary epithelial cells in vitro. Importantly, VE reduced BLM-induced ferritin expression in fibrotic lungs, whereas VE did not exhibit iron chelation properties in fibroblasts or epithelial cells in vitro. Furthermore, VE protected against mitochondrial dysmorphology and normalized mitochondrial protein expression in BLM-PF lungs. Consistently, VE suppressed apoptosis in BLM-PF lungs and pulmonary epithelial cells in vitro. Discussion: Collectively, VE markedly inhibited BLM-induced PF through a complex mechanism, including improving iron metabolism and mitochondrial structure and function, mitigating inflammation, and decreasing the fibrotic functions of fibroblasts and epithelial cells. Therefore, VE presents a highly potential therapeutic against PF due to its multiple protective effects with few side effects.

Investigation of the effects of pulmonary adenomatosis on oxidative dna damage, inflammation, apoptosis, and autophagy in lung tissues in sheep

Pulmonary adenomatosis infections are an infectious and neoplastic disease that affects the respiratory system in sheep. Although the existence and prevalence of this disease have been revealed in studies, there is no definitive treatment today. Diagnosis of the disease; It can be detected by clinical, macroscopic, microscopic, and immunohistochemical methods. Although there are studies reporting the existence and prevalence of the disease today, the pathogenesis has not been fully elucidated. In this study, the effects of pulmonary adenomatosis (PA) infections on lung tissue oxidative DNA damage, inflammation, apoptosis, and autophagy were investigated in sheep. Care was taken to ensure that the lung samples used as negative controls did not show any macroscopic signs of pneumonia. The presence of tumoral foci was examined in the lung tissues to be used as positive control. Then the samples were examined histopathologically. All samples obtained were examined immunohistochemically for the presence of Jaagsiekte Sheep Retrovirus (JSRV) antibodies. In the study, the expression levels of IL1-β, Tnf-α, 8-OHdG, Bcl-2, BAX, Caspase3, LC3B, and LC3A were examined in 6 negative and 12 positive lung tissue samples for PA. In the lung tissues, proliferation of bronchiolar and alveolar epithelial cells, as well as alveolar macrophages and neutrophil leukocyte cell infiltration in their lumens, were observed. It revealed that severe OPA cases had more severe levels of IL1-β, Tnf-α, 8-OHdG, BAX, Caspase3, LC3A, and LC3B expressions than mild cases did. As a result of the research, in cases where the severity of tumor foci due to PA in lung tissues increased; Oxidative stress, inflammation, apoptosis, and autophagy were found to be significantly increased.

HLH Secondary to Influenza

Introduction Hemophagocytic lymphohistiocytosis (HLH) is a pathological condition characterized by excessive inflammation and tissue damage resulting from an aberrant immune system response. HLH can be classified into two distinct categories: primary HLH and secondary HLH. Secondary hemophagocytic lymphohistiocytosis (HLH) is an acquired condition that can be precipitated by various infections, malignancies, or rheumatological disorders. Herein, we present a rare case of HLH secondary to influenza B infection. Case Presentation A 37-year-old who routinely vapes and smokes cannabis presented to the emergency department with subjective fevers, body pains, fatigue, productive cough, shortness of breath, nausea, non-bloody, non-bilious vomiting, and watery diarrhea for one week. He was tachypneic, tachycardic, and febrile (101.1 F). He had loud bibasilar crackles on auscultation. Hb 14.8, total WBC 2.2, platelets 170, AKI with serum creatinine 1.9, and transaminitis with AST/ALT/ALP 130/56/122 U/L were the patient's initial lab results. Rapid influenza, strep, and COVID-19 antigen tests were negative. He exhibits hypoxemia with pH 7.46, pCO2 32.5, pO2 52.1, HCO3 22.9, and FIO2 40%. Urinalysis showed nonsignificant. CRP was 8.3 mg/dL. Negative procalcitonin. chest x-ray and ct showed bilateral diffuse patchy airspace infiltration, suggesting infectious process with mild pleaural effusion. In the critical care unit, he received Antibiotics and inhaled therapy for acute hypoxic respiratory failure with severe ARDS. After deteriorating, he was intubated. The respiratory pathogen panel detected Influenza B. Blood cultures and remaining pneumonia workup were negative. The lab results suggested HLH (table 1). Autoimmune tests were negative. Oseltamivir was given for 5 days. Repeat chest x-rays showed stable pulmonary infiltrates in the right middle and lower lobes, but the patient decompensated clinically with increasing ventilator requirements and dyssynchrony despite heavy sedation, paralytics, and proning and was transferred to a different hospital for ECMO evaluation on day 12. Discussion Primary and secondary HLH: Secondary HLH is caused by infections, malignancies, or rheumatological illnesses, while primary HLH is hereditary. The mortality outcome of HLH is extremely dependent on early detection and treatment 1. Due to the rarity of this disease entity, difficult diagnostic criteria, and concern for alternate diagnoses, internists may be less aware of it. Further complicating the diagnosis is the fact that the first bone marrow biopsy may not always show hemophagocytosis 2. This is why it is important to be cognizant of this diagnosis and it's diagnostic criteria. Our patient was suspected of HLH based on HScore for reactive hemophagocytic syndrome and the newest updated HLH diagnostic criteria (5 of 8 criteria should be met) 6. EBV is the most common viral infection which can cause HLH. CMV, Parvo, HSV, and H1N1 are other infections. HLH-Influenza B connection is poorly documented 7 Only one case of HLH induced by influenza B in a healthy patient was found in literature. To our knowledge, Our 38-year-old patient is the second known case of secondary HLH secondary to Influenza B in a healthy patient. Influenza B seldom causes HLH. This connection in adulthood is poorly researched. Patients with influenza virus infections have significant intestinal apoptosis and reactive hemophagocytic activity in bone marrow, lungs, and liver3. Influenza variants reduce CD8+ T cell cytotoxicity and perforin expression, likely causing HLH syndrome 4. A study suggests that virus-associated hemophagocytic syndrome (VAHS) is a common consequence of severe 2009 influenza A (H1N1) infection and contributes to multiorgan failure and mortality. 9 (36%) of 25 severely ill patients with confirmed 2009 influenza A (H1N1) infection developed VAHS, and 8 (89%) died 5. Conclusion: We present this case to raise awareness among physicians regarding the potential occurrence of hemophagocytic lymphohistiocytosis (HLH) as a complication in adult patients who present with influenza B virus infection accompanied by fever and pancytopenia. The aim is to emphasize the importance of considering HLH as a differential diagnosis in order to facilitate timely identification and initiation of appropriate treatment for this condition.

LncRNA HCG18 loaded by polymorphonuclear neutrophil-secreted exosomes aggravates sepsis acute lung injury by regulating macrophage polarization.

Polymorphonuclear neutrophils (PMNs) exert significant roles in septic acute lung injury (ALI). Accumulating evidence suggests that PMN-derived exosomes (PMN-exo) are a novel subcellular entity that is the fundamental link between PMN-driven inflammation and tissue damage. However, the role of PMN-exo in septic ALI and the underlying mechanisms remain unclear. Tumor necrosis factor-α (TNF-α), a key regulator of innate immunity in septic ALI, was used to induce PMN activation in vitro. Using an in vitro co-culture system, the rat alveolar macrophage cell line NR8383 was co-cultured with TNF-α-stimulated PMN-released exosomes (TNF-α-exo) to further confirm the results of the in vitro studies and explore the underlying mechanisms involved. A septic lung injury model was established by cecal ligation and puncture surgery, and PMN-exo were injected into septic mice through the tail vein, and then lung injury, inflammatory release, macrophage polarization, and apoptosis were examined. The results reported that TNF-α-exo promoted the activation of M1 macrophages after i.p. injection in vivo or co-culture in vitro. Furthermore, TNF-α-exo affected alveolar macrophage polarization by delivering HCG18. Mechanistic studies indicated that HCG18 mediated the function of TNF-α-exo by targeting IL-32 in macrophages. In addition, tail vein injection of si-HCG18 in septic mice significantly reduced TNF-α-exo-induced M1 macrophage activation and lung macrophage death, as well as histological lesions. In conclusion, TNF-α-exo-loaded HCG18 contributes to septic ALI by regulating macrophage polarization. These findings may provide new insights into novel mechanisms of PMN-macrophage polarization interactions in septic ALI and may provide new therapeutic strategies for patients with sepsis.

Fecal microbiota transplantation from HUC-MSC-treated mice alleviates acute lung injury in mice through anti-inflammation and gut microbiota modulation.

Acute lung injury (ALI) is a severe respiratory tract disorder facilitated by dysregulated inflammation, oxidative stress and intestinal ecosystem. Fecal microbiota transplantation (FMT) is a rapid method for gut microbiota (GM) reconstruction. Furthermore, our previous studies have confirmed that human umbilical cord mesenchymal stromal cells (HUC-MSCs) can alleviate ALI by improving GM composition. Therefore, we aimed to explore the efficacy and mechanism of FMT from HUC-MSCs-treated mice on ALI. In brief, fresh feces from HUC-MSCs-treated mice were collected for FMT, and the mice were randomly assigned into NC, FMT, LPS, ABX-LPS, and ABX-LPS-FMT groups (n = 12/group). Subsequently, the mice were administrated with antibiotic mixtures to deplete GM, and given lipopolysaccharide and FMT to induce ALI and rebuild GM. Next, the therapeutic effect was evaluated by bronchoalveolar lavage fluid (BALF) and histopathology. Immune cells in peripheral blood and apoptosis in lung tissues were measured. Furthermore, oxidative stress- and inflammation-related parameter levels were tested in BALF, serum, lung and ileal tissues. The expressions of apoptosis-associated, TLR4/NF-κB pathway-associated, Nrf2/HO-1 pathway related and tightly linked proteins in the lung and ileal tissues were assessed. Moreover, 16S rRNA was conducted to assess GM composition and distribution. Our results revealed that FMT obviously improved the pathological damage of lung and ileum, recovered the immune system of peripheral blood, decreased the cell apoptosis of lung, and inhibited inflammation and oxidative stress in BALF, serum, lung and ileum tissues. Moreover, FMT also elevated ZO-1, claudin-1, and occludin protein expressions, activating the Nrf2/HO-1 pathway but hindering the TLR4/NF-κB pathway. Of note, the relative abundances of Bacteroides, Christensenella, Coprococcus, and Roseburia were decreased, while the relative abundances of Xenorhabdus, Sutterella, and Acinetobacter were increased in the ABX-LPS-FMT group. FMT from HUC-MSCs-treated mice may alleviate ALI by inhibiting inflammation and reconstructing GM, additionally, we also found that the TLR4/NF-κB and Nrf2/HO-1 pathways may involve in the improvement of FMT on ALI, which offers novel insights for the functions and mechanisms of FMT from HUC-MSCs-treated mice on ALI.

Recombinant CXCL17 Treatment Alleviates Hyperoxia-Induced Lung Apoptosis and Inflammation In Vivo and Vitro by Activating the AKT Pathway: A Possible Therapeutic Approach for Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD), caused by hyperoxia exposure, is the most common complication affecting preterm infants. The C-X-C motif chemokine ligand 17 (CXCL17) belongs to the chemokine family that plays important roles in various processes, but the function in BPD is unknown. Elevated serum CXCL17 levels were observed in human premature infants with hyperoxia-induced lung injury, suggesting that CXCL17 might be involved in BPD. To further validate our speculation, studies were conducted in a hyperoxia-induced lung injury mouse model and primary murine alveolar epithelial cells Type II (T2AEC) cells exposed to hyperoxia. RT-qPCR and western blot were used to validate CXCL17 expression in newborn mice. Hyperoxia exposure-induced lung injury was determined by assessing the lung wet-weight/dry-weight ratio and histological changes. Oxidative stress and inflammatory factors were examined by ELISA assay and RT-qPCR. Reactive oxygen species (ROS) level was evaluated by DHE staining. Apoptosis was assessed by TUNEL staining and western blot. The results showed that hyperoxia exposure increased CXCL17 levels in newborn mice pups. Hyperoxia exposure increased lung wet-weight/dry-weight ratio, increased alveolar diameter and enlarged alveoli, and reduced surfactant protein C expression. However, recombinant CXCL17 (rCXCL17) treatment alleviated hyperoxia-induced lung injury. rCXCL17 treatment inhibited hyperoxia-induced inflammation, oxidative stress, and apoptosis in neonatal mice. These results were further verified in T2AEC cells. Additionally, rCXCL17 treatment activated the AKT pathway, which is a protective pathway in BPD. Collectively, rCXCL17 alleviates hyperoxia-induced lung injury in neonatal mice by activating the AKT pathway, indicating that CXCL17 may be a promising target for BPD therapy.

Activation of Nrf2/ARE pathway by Anisodamine (654-2) for Inhibition of cellular aging and alleviation of Radiation-Induced lung injury

BackgroundRadiation-induced lung injury (RILI) is a common side effect of thoracic tumor radiotherapy, including early-stage radiation-induced lung injury (RP) and late-stage radiation-induced pulmonary fibrosis (RIPF). Currently, it is urgently needed to clarify the pathogenesis of RILI and find safe and effective RILI treatment methods. Irradiation causes DNA damage and oxidative stress in tissues and cells, induces cellular senescence, and promotes the occurrence and development of RILI. In recent years, Anisodamine (654-2) has shown potential therapeutic value in acute lung injury, acute kidney injury, chlamydial pneumonia, and COVID-19. However, there is currently no research on the mechanism of 654-2-mediated cellular senescence and its preventive and therapeutic effects on RILI. PurposeThis study aimed to investigate the protective effect and mechanism of 654-2 on X-ray-induced RILI. MethodsIn vivo experiments involved a mouse RILI model with 18 Gy X-ray irradiation. Mice were divided into control, model, medication (control + 654-2), and treatment (model + 654-2) groups. And mice in medication and treatment groups were intraperitoneal injection of 5 mg/kg 654-2 every other day until being sacrificed at week 6. In vitro experiments used MLE-12 cells irradiated with 16 Gy and divided into control, model, and model + 654-2（2 μM and 10 μM） groups. Various assays were performed to evaluate lung tissue morphology, fibrosis, apoptosis, cytokine expression, cellular senescence, protein expression, and antioxidant capacity. Results654-2 mitigated pulmonary pathological damage, inflammation, DNA damage, cellular senescence, and apoptosis in RILI mice and MLE-12 cells. It restored epithelial cell proliferation ability and enhanced antioxidant capacity. Additionally, 654-2 activated the Nrf2/ARE pathway, increased Nrf2 phosphorylation, and upregulated antioxidant gene expression. Inhibition of Nrf2 reversed the effects of 654-2 on ROS production, antioxidant capacity, and cell senescence. Conclusion654-2 can activate the Nrf2/ARE pathway, enhance cellular antioxidant capacity, and inhibit cellular senescence, thereby exerting a protective effect against RILI.

Exogenous Apelin-13 Administration Ameliorates Cyclophosphamide- Induced Oxidative Stress, Inflammation, and Apoptosis in Rat Lungs.

Apelin-13 is an endogenous adipocytokine known for its antioxidant, antiinflammatory, and antiapoptotic properties. We aimed to investigate the possible protective effects of exogenous Apelin-13 administration on oxidative stress, inflammation, and apoptosis induced by the cytotoxic agent cyclophosphamide (CP) in the lungs. Twenty-four male Wistar albino rats were divided into four groups: Control (saline), CP (200 mg/kg), Apelin-13 (10 μg/kg/day), and CP+Apelin-13. CP was administered as a single dose on the fifth day, and apelin-13 was administered intraperitoneally for five days. Total oxidant status (TOS), total antioxidant status (TAS), and lipid peroxidation were determined with spectrophotometry, TNFα and IL1β were determined with ELISA, APJ, Sirt1, NF-κB, and p53 mRNA expressions were determined with qRT-PCR, cytochrome (Cyt) C and caspase-3 protein expressions were studied with western blotting in lung tissues. The oxidative stress index (OSI) was also calculated. Furthermore, serum surfactant protein-D (SP-D) and Krebs von den Lungen-6 (KL-6) levels were measured with ELISA. Compared to the control group, TOS, OSI, lipid peroxidation, TNFα, IL1β, cyt C, caspase-3, APJ, NF-κB, and p53 were higher, and Sirt1 was lower in the lung tissue of rats in the CP group. Serum KL-6 and SP-D levels were higher in the CP group. Co-administration of CP with Apelin-13 completely reversed the changes induced by CP administration. Exogenous Apelin-13 treatment protected lung tissue against injury by inhibiting cyclophosphamide-induced oxidative stress, inflammation, and apoptosis. This protective effect of apelin-13 was accompanied by upregulation of the Sirt1 and downregulation of NF-κB/p53 in the lungs.