Induced Lung Damage Research Articles

Diagnosis and Management of Drug-Induced Interstitial Lung Disease in the context of Anti-Cancer Therapy: a Multidisciplinary Viewpoint by Portuguese Experts.

Drug-induced interstitial lung disease (DI-ILD) is a significant complication in patients undergoing treatment with certain anti-cancer therapies, with incidence rates rising, particularly with newer drugs such as trastuzumab-deruxtecan, which may impact their safe and effective use. Although the exact pathophysiological mechanisms remain unknown, and different drugs may induce lung damage through different pathways, the most recognized mechanisms are cytotoxic- and immune-mediated effects. Multidisciplinary teams play a crucial role in the diagnosis, management, and prevention of DI-ILD. Given the wide variability in the onset of DI-ILD, which may occur within the first few days of treatment or months after, patient education and clinician training are essential for early detection and improved outcomes. Moreover, the diagnostic confirmation requires the exclusion of alternative causes through clinical, imaging and bronchoscopy evaluation. Treatment strategies largely depend on the grade of severity of the clinical manifestations of DI-ILD, ranging from interruption or discontinuation of the offending drug to corticosteroid therapy and hospitalization for appropriate monitoring. Nonetheless, further research is needed to better understand the impact of emerging anti-cancer drugs on DI-ILD and to establish standardized management protocols.

Relationship between fat embolism and endothelial glycocalyx

Fat embolism (FE) is acknowledged as one of the significant causes of sudden death following traumatic injury. To clarify the relevance of vascular endothelial glycocalyx (EGC) damage and FE, temporal changes in the mRNA levels of inflammatory cytokines associated with EGC components were investigated in an experimental fat embolization rat model. Nine-week-old rats were used as FE models through triolein injection (TO) and femoral fracture (FX), and physiological saline was administered to the control group. RT-qPCR and fat staining were performed. The target genes were Il6, Il10, Tnf, Elane, Sdc1, Sdcbp, Vcan, Hyal1, Fn1, and CD14. Notably, FE was detected in 100% and 5.6% of the TO and FX groups, respectively, using fat staining. Bimodal peaks in the mRNA expression levels of Sdc1, Tnf, Elane, IL6, and IL10 were observed 4 and 20 h after treatment in both groups. In the TO group, mRNA expression peaked at 4 h and then declined to the lowest level at 16 h. The incidence of fat emboli due to trauma was consistent with that reported in previous studies. Bimodal mRNA peaks may correspond to FE progression, in which physical obstructions are followed by biochemical reactions. The fluctuation in Sdc1 expression suggests that the initial peak resulted from physical EGC damage. The subsequent peak could be because of EGC damage caused by the secretion of inflammatory cytokines induced by oleic acid from lipid droplet decomposition. These results suggest that EGC disorders caused by lipid droplets may induce lung damage during FE.

Hexamerization: explaining the original sin of IgG-mediated complement activation in acute lung injury.

Although antibody-mediated lung damage is a major factor in transfusion-related acute lung injury (ALI), autoimmune lung disease (for example, coatomer subunit α [COPA] syndrome), and primary graft dysfunction following lung transplantation, the mechanism by which antigen-antibody complexes activate complement to induce lung damage remains unclear. In this issue of the JCI, Cleary and colleagues utilized several approaches to demonstrate that IgG forms hexamers with MHC class I alloantibodies. This hexamerization served as a key pathophysiological mechanism in alloimmune lung injury models and was mediated through the classical pathway of complement activation. Additionally, the authors provided avenues for exploring therapeutics for this currently hard-to-treat clinical entity that has several etiologies but a potentially focused mechanism.

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.

A Retrospective Study on Mucormycosis and Other Fungal Infections Associated With COVID-19

A drastic increase in mucormycosis and other opportunistic infections was observed during the Covid-19 pandemic owing to multisystem involvement and related Immunosuppression. This retrospective study was carried out among SARS-COV-2 infected patients having invasive fungal infections [IFI] admitted to a tertiary care hospital in the southern part of India, for one year from August 2020. Among a total of 115 suspected cases, 54 patients were diagnosed to have IFI, during or immediately after Covid 19 disease. The most common fungal pathogens isolated were Mucorales (57.4%) followed by Aspergillus spp. (20.3%), Candida spp. (9.2%) and mixed infections (13.1%). Important predisposing factors identified were diabetes mellitus (70.7%), prolonged use of corticosteroids (85%), and administration of broad-spectrum antibiotics (90%). The predominant species identified among the diagnosed mucormycosis cases were Rhizopus spp. (54%) and Mucor spp. (25%); the site of involvement was paranasal sinus (70.1%), and rhino-orbital in 48.7% of the cases. Increased incidence of invasive Aspergillus infection in COVID-19 was seen mainly among ICU patients on ventilators, with Covid-19 induced lung damage. Common presentations were Chronic Pulmonary Aspergillosis, Rhino sinusitis, and Asthma. Of the total IFI, 9.2 % were caused by Candida spp. Of which 75% were due to Non- albicans candida species. Candidemia was the major presentation observed (90%). Of the patients with IFI, 90 % of them recovered, and the rest of them (7.4%) succumbed to infection. Of the patients with rhino-orbital mucormycosis who survived, 10 (39 %) had facial disfigurement and 11 (45 %) had a loss of vision.

Lactate exacerbates lung damage induced by nanomicroplastic through the gut microbiota–HIF1a/PTBP1 pathway

Exposure to nanomicroplastics (nano-MPs) can induce lung damage. The gut microbiota is a critical modulator of the gut–lung axis. However, the mechanisms underlying these interactions have not been elucidated. This study explored the role of lactate, a key metabolite of the microbiota, in the development of lung damage induced by nano-MPs (LDMP). After 28 days of exposure to nano-MPs (50–100 nm), mice mainly exhibited damage to the lungs and intestinal mucosa and dysbiosis of the gut microbiota. Lactate accumulation was observed in the lungs, intestines and serum and was strongly associated with the imbalance in lactic acid bacteria in the gut. Furthermore, no lactate accumulation was observed in germ-free mice, while the depletion of the gut microbiota using a cocktail of antibiotics produced similar results, suggesting that lactate accumulation in the lungs may have been due to changes in the gut microbiota components. Mechanistically, elevated lactate triggers activation of the HIF1a/PTBP1 pathway, exacerbating nano-MP-induced lung damage through modulation of the epithelial–mesenchymal transition (EMT). Conversely, mice with conditional knockout of Ptbp1 in the lungs (Ptbp1flfl) and PTBP1-knockout (PTBP1-KO) human bronchial epithelial (HBE) cells showed reversal of the effects of lactate through modulation of the HIF1a/PTBP1 signaling pathway. These findings indicate that lactate is a potential target for preventing and treating LDMP.

Preliminary PET imaging of [11C]evobrutinib in mouse models of colorectal cancer, SARS-CoV-2, and lung damage: Radiosynthesis via base-aided palladium-NiXantphos-mediated 11C-carbonylation.

Evobrutinib is a second-generation, highly selective, irreversible Bruton's tyrosine kinase (BTK) inhibitor that has shown efficacy in the autoimmune diseases arthritis and multiple sclerosis. Its development as a positron emission tomography (PET) radiotracer has potential for in vivo imaging of BTK in various disease models including several cancers, severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), and lipopolysaccharide (LPS)-induced lung damage. Herein, we report the automated radiosynthesis of [11C]evobrutinib using a base-aided palladium-NiXantphos-mediated 11C-carbonylation reaction. [11C]Evobrutinib was reliably formulated in radiochemical yields of 5.5 ± 1.5% and a molar activity of 34.5 ± 17.3 GBq/μmol (n =12) with 99% radiochemical purity. Ex vivo autoradiography studies showed high specific binding of [11C]evobrutinib in HT-29 colorectal cancer mouse xenograft tissues (51.1 ± 7.1%). However, in vivo PET/computed tomography (CT) imaging with [11C]evobrutinib showed minimal visualization of HT-29 colorectal cancer xenografts and only a slight increase in radioactivity accumulation in the associated time-activity curves. In preliminary PET/CT studies, [11C]evobrutinib failed to visualize either SARS-CoV-2 pseudovirus infection or LPS-induced injury in mouse models. In conclusion, [11C]evobrutinib was successfully synthesized by 11C-carbonylation and based on our preliminary studies does not appear to be a promising BTK-targeted PET radiotracer in the rodent disease models studied herein.

Thymoquinone attenuates doxorubicin-induced lung damage via heat shock proteins, inflammation and endoplasmic reticulum stress

The aim of this study is to determine possible therapeutic effects of THQ on doxorubicin induced lung damage in rats. Rats were divided into five groups (n = 8): control, THQ, olive oil, DOX (a single dose of 15 mg/kg intraperitoneally (i.p.) on seventh day of the experiment), and DOX+THQ (10 mg/kg THQ per day and 15 mg/kg DOX i.p. on seventh day). Animals were euthanized, and lung tissues were evaluated histopathologically. Caspase3, GRP78, GADD153, HSP90, HSP70, PCNA, COX2 and TNFα immunostaining were performed to determine the expression levels of these proteins among groups. TUNEL method was used for evaluation of apoptotic index. Moreover, total antioxidant status (TAS), total oxidant status (TOS) and IL6 in lung tissue were measured by ELISA assay. The DOX group had histopathological deterioration compared to the control group. There was an increase in apoptotic index, caspase 3, GRP78, GADD153, HSP90, HSP70, PCNA, COX2 and TNFα expressions in the DOX group. While TAS level of the DOX group decreased, IL6 and TOS level increased when compared with the other groups. However, there was improvement in lung tissue in DOX + THQ group compared to the DOX group. There was a decrease in apoptotic index, caspase 3, GRP78, GADD153, HSP90, HSP70, PCNA, COX2, TNFα expressions and TOS, IL6 in DOX+THQ group compared to the DOX group. We suggest that THQ can be used as a protective agent to reduce the toxic effects of DOX.

Comparison of the Protective Effect of Alpha Lipoic Acid and Quercetin in Methotrexate- Induced Lung Damage

Comparison of the Protective Effect of Alpha Lipoic Acid and Quercetin in Methotrexate- Induced Lung Damage

Pseudomonas stutzeri PM101005 inhaled with atmospheric particulate matter induces lung damage through inflammatory responses

Atmospheric particulate matter (PM) contains a mixture of chemical and biological elements that pose threat to human health by increasing susceptibility to respiratory diseases. Although the identification of the microorganisms composing the PM has been assessed, their immunological impacts are still questionable. Here, we examined the mechanisms responsible for the pathogenicity of Pseudomonas stutzeri PM101005 (PMPS), a bacterium isolated from fine dust, in lung epithelial cells, alveolar cells, and macrophages. Relative to its comparative strain Pseudomonas stutzeri (PS), infections with PMPS induced higher production of inflammatory cytokines and chemokines, mediated by the activation of NF-κB and MAPK signaling pathways. Additionally, with three-dimensional (3D) airway spheroids which mimic the human bronchial epithelium, we confirmed that PMPS infections lead to relatively higher induction of pro-inflammatory cytokines than PM infections. Consistent results were observed in murine models as the infections with PMPS provoked greater inflammatory responses than the infections with PS. These PMPS-induced responses were mediated by the signaling pathways of the Toll-like receptors (TLRs), which regulated PMPS infection and played an important role in the expression of the antibiotic peptide β-defensin 3 (BD3) that suppressed PMPS proliferation. Moreover, PM pretreatment enhanced inflammatory responses and tissue damage of PMPS, while reducing BD3 expression. Overall, these results indicate that PM-isolated PMPS induce TLR-mediated inflammatory responses in lung tissues, and contributes to the understanding of the etiology of PM-induced respiratory damage.

Therapeutic role of N-acetyl cysteine (NAC) for the treatment and/or management of SARS-CoV-2-induced lung damage in hamster model

Oxidative stress by reactive oxygen species (ROS) has been hypothesized to be the major mediator of SARS-CoV-2-induced pathogenesis. During infection, the redox homeostasis of cells is altered as a consequence of virus-induced cellular stress and inflammation. In such scenario, high levels of ROS bring about the production of pro-inflammatory molecules like IL-6, IL-1β, etc. that are believed to be the mediators of severe COVID-19 pathology. Based on the known antioxidant, anti-inflammatory, mucolytic and antiviral properties of NAC, it has been hypothesized that NAC will have beneficial effects in COVID-19 patients. In the current study efforts have been made to evaluate the protective effect of NAC in combination with remdesivir against SARS-CoV-2 induced lung damage in the hamster model. The SARS-CoV-2 infected animals were administered with high (500 mg/kg/day) and low (150 mg/kg/day) doses of NAC intraperitoneally with and without remdesivir. Lung viral load, pathology score and expression of inflammatory molecules were checked by using standard techniques. The findings of this study show that high doses of NAC alone can significantly suppress the SARS-CoV-2 mediated severe lung damage (2 fold), but on the contrary, it fails to restrict viral load. Moreover, high doses of NAC with and without remdesivir significantly suppressed the expression of pro-inflammatory genes including IL-6 (4.16 fold), IL-1β (1.96 fold), and TNF-α (5.55 fold) in lung tissues. Together, results of this study may guide future preclinical and clinical attempts to evaluate the efficacy of different doses and routes of NAC administration with or without other drugs against SARS-CoV-2 infection.

H1N1 influenza virus dose dependent induction of dysregulated innate immune responses and STAT1/3 activation are associated with pulmonary immunopathological damage

ABSTRACT Influenza A virus (IAV) infection poses a substantial challenge and causes high morbidity and mortality. Exacerbated pulmonary inflammatory responses are the major causes of extensive diffuse alveolar immunopathological damage. However, the relationship between the extent of cytokine storm, neutrophils/macrophages infiltration, and different IAV infection dose and time still needs to be further elucidated, and it is still unclear whether the signal transduction and transcriptional activator 1/3 (STAT1/3) signalling pathway plays a beneficial or detrimental role. Here, we established a mouse model of high- and low-dose pH1N1 infection. We found that pH1N1 infection induced robust and early pathological damage and cytokine storm in an infection dose- and time-dependent manner. High-dose pH1N1 infection induced massive and sustained recruitment of neutrophils as well as a higher ratio of M1:M2, which may contribute to severe lung immunopathological damage. pH1N1 infection activated dose- and time-dependent STAT1 and STAT3. Inhibition of STAT1 and/or STAT3 aggravated low-dose pH1N1 infection, induced lung damage, and decreased survival rate. Appropriate activation of STAT1/3 provided survival benefits and pathological improvement during low-dose pH1N1 infection. These results demonstrate that high-dose pH1N1 infection induces robust and sustained neutrophil infiltration, imbalanced macrophage polarization, excessive and earlier cytokine storm, and STAT1/3 activation, which are associated with pulmonary dysregulated proinflammatory responses and progress of acute lung injury. The severe innate immune responses may be the threshold at which protective functions give way to immunopathology, and assessing the magnitude of host innate immune responses is necessary in adjunctive immunomodulatory therapy for alleviating influenza-induced pneumonia.

Dexpanthenol Inhibits Inflammation and Apoptosis in LPS-Induced Acute Lung Injury by Reducing Increased VCAM-1 and Caspase-3 Expressions in Rats

This study aims to investigate the effects of Dexpanthenol (Dex), a stable alcoholic analogue of D-pantothenic acid which has anti-oxidant, antiapoptotic, and antiinflammatory properties, on lipopolysaccharide (LPS)-induced lung damage via caspase-3 (cas-3) and vascular cell adhesion molecule-1 (VCAM-1) levels. According to the experimental plan of study, thirty-two Wistar Albino species rats were distributed randomly into four groups as control, LPS (5 mg/kg, intraperitoneally (i.p), single dose), LPS (30 minutes before last Dex treatment) + Dex (500 mg/kg, i.p, for 3 days) and Dex. After six hours of LPS application, lung tissues of the rats were taken for histopathological, immunohistochemical and biochemical examinations. According to results of the study, LPS causes hyperemia, neutrophil leukocyte chemotaxis and thickened septal tissue on lung. Inducing inflammation by increasing VCAM-1 levels and triggers apoptosis by increasing cas-3 levels in lung tissue. In addition, LPS decreased total antioxidant status levels, which is a marker of anti-oxidant capacity, and increased oxidative stress index and total oxidant status values, which are indicators of oxidative stress. Dex has shown its effect by reversing all these alterations and normalizing the values. These results suggest that Dex can be used as a preservative to reduce LPS-induced acute toxicity in the lung.

Nimotuzumab Increases the Recovery Rate of Severe and Critical COVID-19 Patients: Evaluation in the Real-World Scenario.

EGFR signaling is an important regulator of SARS-CoV induced lung damage, inflammation and fibrosis. Nimotuzumab is a humanized anti-EGFR antibody registered for several cancer indications. An expanded access study was conducted to evaluate the safety and recovery rate of severe and critical patients with confirmed SARS-CoV-2 infection, treated with nimotuzumab in combination with the standard of care in the real-world scenario. The antibody was administered as an intravenous infusions every 72 h, up to 5 doses. In order to assess the impact of nimotuzumab, the recovery rate was compared with a paired retrospective cohort. Control patients received standard treatment according the national protocol but not nimotuzumab. Overall, 1,151 severe or critical patients received nimotuzumab in 21 hospitals of Cuba. Median age was 65 and 773 patients had at least one comorbidity. Nimotuzumab was very well-tolerated and mild or moderate adverse events were detected in 19 patients. 1,009 controls matching with the nimotuzumab patients, were selected using a “propensity score” method. The 14-day recovery rate of the nimotuzumab cohort was 72 vs. 42% in the control group. Controls had a higher mortality risk (RR 2.08, 95% CI: 1.79, 2.38) than the nimotuzumab treated patients. The attributable fraction was 0.52 (95% CI: 0.44%; 0.58), and indicates the proportion of deaths that were prevented with nimotuzumab. Our preliminary results suggest that nimotuzumab is a safe antibody that can reduce the mortality of severe and critical COVID-19 patients.

Protective effects of intranasal curcumin on silica-induced lung damage

ObjectiveBeing anti-inflammatory and an antioxidant in nature, curcumin has been studied for its anti-asthmatic effects, but its impact on silicosis has not been investigated before. It is a form of occupational lung illness caused by inhaling crystalline silica. It is particularly common among those who work in construction-related sectors. Therefore, present study has been undertaken to investigate impact of intranasal curcumin on silica induced lung damage in mice model of silicosis. Materials and methodsMice model of silicosis was developed by intranasal silica instillation (2.5 mg/mice) for different durations mainly 7, 14 and 21 days, where the longest duration of silica exposure (21 days) mimics chronic occupational exposure of silica dust leading to silicosis. Curcumin (5 mg/kg,i.n) and /or dexamethasone, a known corticosteroid (10 mg/kg,i.p) was administered an hour prior to silica administration. ResultsPresent study revealed silica induced lung damage in the mice model of silicosis characterized by airway inflammation, collagen deposition and enhanced expression of fibrosis markers (MMP-9, α-SMA, Hydroxyproline), which were significantly reduced in curcumin treatment groups. Inhibitory effects of curcumin were compared with standard drug, dexamethasone, a corticosteroid and was found better in protecting structural alterations in the lung.Damaged and abnormal mitochondria (enlarged and irregular shapes) were observed in silicosis group which were reduced in curcumin and dexamethasone treatment groups as revealed in transmission electron microscopic studies. ConclusionsPresent study shows protective effects of intranasal curcumin on silica-induced airway inflammation and structural changes thereby lung damage. Hence, it can be considered as an alternative and complementary medication for silicosis.

Curcumin alleviated lipopolysaccharide-induced lung injury via regulating the Nrf2-ARE and NF-κB signaling pathways in ducks.

Under the intensive modern poultry farming system, the lung of duck is one of the main target organs for various bacterial and viral infections. Curcumin is a kind of natural polyphenol compound for which various beneficial biological functions exist, including being an anti-inflammatory, antioxidant, and antiviral. The aim of this work was to investigate the mechanism of curcumin-alleviated lipopolysaccharide (LPS)-induced lung damage by the nuclear erythroid 2-related factor 2 (Nrf2)-antioxidant reaction element (ARE) and nuclear factor kappa B (NF-κB) signaling pathway in ducks. In total, 450 one-day-old male specific pathogen-free ducks were randomly assigned into three dietary treatments: CON, basal diet; LPS, basal diet + LPS treatment; LPS + CUR, basal diet + LPS + 500 mg kg-1 of curcumin. At the end of the experiment (21 days), ducks in LPS treatment were challenged with 5mg LPS per kilogram of body weight and the other two treatments were injected with the same dose of phosphate-buffered saline solution. The results showed that LPS caused acute inflammation, oxidation stress, and lung injury. Dietary addition of curcumin significantly relieved the oxidation stress and inflammation parameters. Moreover, the results showed that remission may be through the signaling pathways of both Nrf2-ARE and NF-κB. In conclusion, dietary supplementation of 500 mg kg-1 of curcumin exhibited a lung-protective effect in ducks. This experiment broadens the mode of metabolism actions of curcumin in the target organs and provides an insight for the application of curcumin in waterfowl feed. © 2022 Society of Chemical Industry.

Diagnostic Value of 18F-NOTA-FAPI PET/CT in a Rat Model of Radiation-Induced Lung Damage.

In this study, we explore the diagnostic value of a novel PET/CT imaging tracer that specifically targets fibroblast activation protein (FAP), 18F-NOTA-FAPI, in a radiation induced lung damage (RILD) rat model. High focal radiation (40, 60, or 90 Gy) was administered to a 5-mm diameter area of the right lung in Wistar rats for evaluation of RILD induction. Lung tissues exposed to 90 Gy radiation were scanned with 18F-NOTA-FAPI PET/CT and with 18F-FDG. Dynamic 18F-NOTA-FAPI PET/CT scanning was performed on day 42 post-irradiation. After in vivo scanning, lung cryosections were prepared for autoradiography, hematoxylin and eosin (HE) and immunohistochemical (IHC) staining. An animal model of RILD was established and validated by histopathological analysis. On 18F-NOTA-FAPI PET/CT, RILD was first observed on days 42, 35 and 7 in the 40, 60 and 90 Gy groups, respectively. After treatment with 90 Gy, 18F-NOTA-FAPI uptake in an area of RILD emerged on day 7 (0.65 ± 0.05%ID/ml) and reappeared on day 28 (0.81 ± 0.09%ID/ml), remaining stable for 4–6 weeks. Autoradiography and HE staining IHC staining revealed that 18F-NOTA-FAPI accumulated mainly in the center of the irradiated area. IHC staining confirmed the presence of FAP+ macrophages in the RILD area, while FAP+ fibroblasts were observed in the peripheral area of irradiated lung tissue. 18F-NOTA-FAPI represents a promising radiotracer for in vivo imaging of RILD in a dose- and time-dependent manner. Noninvasive imaging of FAP may potentially aiding in the clinical management of radiotherapy patients.

Hydrogen Repairs LPS-Induced Endothelial Progenitor Cells Injury via PI3K/AKT/eNOS Pathway.

Endotoxins and other harmful substances may cause an increase in permeability in endothelial cells (ECs) monolayers, as well as ECs shrinkage and death to induce lung damage. Lipopolysaccharide (LPS) can impair endothelial progenitor cells (EPCs) functions, including proliferation, migration, and tube formation. EPCs can migrate to the damaged area, differentiate into ECs, and participate in vascular repair, which improves pulmonary capillary endothelial dysfunction and maintains the integrity of the endothelial barrier. Hydrogen (H2) contributes to the repairment of lung injury and the damage of ECs. We therefore speculate that H2 protects the EPCs against LPS-induced damage, and it’s mechanism will be explored. The bone marrow-derived EPCs from ICR Mice were treated with LPS to establish a damaged model. Then EPCs were incubated with H2, and treated with PI3K inhibitor LY294002 and endothelial nitric oxide synthase (eNOS) inhibitor L-NAME. MTT assay, transwell assay and tube formation assay were used to detect the proliferation, migration and angiogenesis of EPCs. The expression levels of target proteins were detected by Western blot. Results found that H2 repaired EPCs proliferation, migration and tube formation functions damaged by LPS. LY294002 and L-NAME significantly inhibited the repaired effect of H2 on LPS-induced dysfunctions of EPCs. H2 also restored levels of phosphor-AKT (p-AKT), eNOS and phosphor-eNOS (p-eNOS) suppressed by LPS. LY294002 significantly inhibited the increase of p-AKT and eNOS and p-eNOS expression exposed by H2. L-NAME significantly inhibited the increase of eNOS and p-eNOS expression induced by H2. H2 repairs the dysfunctions of EPCs induced by LPS, which is mediated by PI3K/AKT/eNOS signaling pathway.

Unveiling the Pathologic Response of Cardiac Fibroblasts During Aspergillus fumigatus Pulmonary Infections

Various adverse cardiovascular events have been associated with lung damage as a result of pathological infections followed by chronic inflammation. In this context, several recent studies report severe cardiovascular complications after pulmonary infection by SARS‐CoV‐2. Therefore, determining the physiological link between abnormal pulmonary and cardiac function is an emerging clinical need in the cardiovascular field. The main limitation of these studies has been the lack of specific genetic tools and mouse models to study the cellular and molecular mechanisms that regulate the lung‐heart interactions. To induce lung damage we utilized a common airborne environmental fungus, Aspergillus fumigatus (AF), which is an opportunistic pathogen that establishes pathological infection in the lung if the immune system is compromised. However, in immunocompetent animals, transient stress to the lung is still detectable before clearance via immune cells. Our lab has discovered that pulmonary fibroblasts (PFs), typically associated with the maintenance and production of the extracellular matrix, activate in response to inhaled AF spores and modulate the immune response. Moreover, we have also observed activation of cardiac fibroblasts (CFs) in response to the pulmonary AF infection. Therefore, we hypothesized that pulmonary infection leads to cardiac stress, resulting in the activation and pathological response of CFs, and subsequently result in myocardial remodeling, fibrosis, and disease. To test our hypothesis we used our recently developed and described in vivo cre‐loxP lineage tracing mouse lines to specifically tag and manipulate all activated fibroblast during infection, clearing and reinfection. Our data show that CFs can activate after an acute inhalation of AF spores which are quickly cleared in immunocompetent mice with no pathological lung damage. Moreover, subsequent asymptomatic chronic AF infections result in the accumulation of PF and CF pathologic activation. These results reveal a cellular novel link between pulmonary infection and its impact on cardiovascular events.

Amifostine analog, DRDE-30, alleviates radiation induced lung damage by attenuating inflammation and fibrosis

BackgroundRadiotherapy of thoracic neoplasms and accidental radiation exposure often results in pneumonitis and fibrosis of lungs. Here, we investigated the potential of amifostine analogs: DRDE-07, DRDE-30, and DRDE-35, in alleviating radiation-induced lung damage. MethodsC57BL/6 mice were exposed to 13.5 Gy thoracic irradiation, 30 min after intraperitoneal administration of the analogs, and assessed for modulation of the pathological response at 12 and 24 weeks. Key findingsDRDE-07, DRDE-30 and DRDE-35 increased the survival of irradiated mice from 20% to 30%, 80% and 70% respectively. Reduced parenchymal opacity (X-ray CT) in the lungs of DRDE-30 pre-treated mice corroborated well with the significant decrease in Ashcroft score (p < 0.01). Two-fold increase in SOD and catalase activities (p < 0.05), coupled with a 50% increase in GSH content and a 60% decrease in MDA content (p < 0.05) suggested restoration of the antioxidant defence system. A 20% to 40% decrease in radiation-induced apoptotic and mitotic death in the lung tissue (micronuclei: p < 0.01), resulted in attenuated lung and vascular permeability (FITC-Dextran leakage) by 50% (p < 0.01), and a commensurate reduction (~50%) in leukocyte infiltration in the injured tissue (p < 0.05). DRDE-30 abrogated the activation of pro-inflammatory NF-κB and p38/MAPK signaling cascades, suppressing the release of pro-inflammatory cytokines (IL-1β: p < 0.05; TNF-α: p < 0.05; IL-6: p < 0.05) and up-regulation of CAMs on the endothelial cell surface. Reduction in hydroxyproline content (p < 0.01) and collagen suggested inhibition of lung fibrosis which was associated with attenuation of TGF-β/Smad pathway-mediated-EMT. ConclusionDRDE-30 could be a potential prophylactic agent against radiation-induced lung injury.