Epithelial-mesenchymal transition in chemoradiation-induced lung damage: Mechanisms and potential treatment approaches.

Pulmonary injury is one of the key restricting factors for the therapy of malignancies with chemotherapy or following radiotherapy for chest cancers. The lung is a sensitive organ to some severely toxic antitumor drugs, consisting of bleomycin and alkylating agents. Furthermore, treatment with radiotherapy may drive acute and late adverse impacts on the lung. The major consequences of radiotherapy and chemotherapy in the lung are pneumonitis and fibrosis. Pneumonitis may arise some months to a few years behind cancer therapy. However, fibrosis is a long-term effect that appears years after chemo/or radiotherapy. Several mechanisms such as oxidative stress and severe immune reactions are implicated in the progression of pulmonary fibrosis. Epithelial-mesenchymal transition (EMT) is offered as a pivotal mechanism for lung fibrosis behind chemotherapy and radiotherapy. It seems that pulmonary fibrosis is the main consequence of EMT after chemo/radiotherapy. Several biological processes, consisting of the liberation of pro-inflammatory and pro-fibrosis molecules, oxidative stress, upregulation of nuclear factor of κB and Akt, epigenetic changes, and some others, may participate in EMT and pulmonary fibrosis behind cancer therapy. In this review, we aim to discuss how chemotherapy or radiotherapy may promote EMT and lung fibrosis. Furthermore, we review potential targets and effective agents to suppress EMT and lung fibrosis after cancer therapy.

In vitro and in vivo protective potential of quercetin-3-glucuronide against lipopolysaccharide-induced pulmonary injury through dual activation of nuclear factor-erythroid 2 related factor 2 and autophagy.

In vitro and in vivo models of lipopolysaccharide (LPS)-induced pulmonary injury, quercetin-3-glucuronide (Q3G) has been previously revealed the lung-protective potential via downregulation of inflammation, pyroptotic, and apoptotic cell death. However, the upstream signals mediating anti-pulmonary injury of Q3G have not yet been clarified. It has been reported that concerted dual activation of nuclear factor-erythroid 2 related factor 2 (Nrf2) and autophagy may prove to be a better treatment strategy in pulmonary injury. In this study, the effect of Q3G on antioxidant and autophagy were further investigated. Noncytotoxic doses of Q3G abolished the LPS-caused cell injury, and reactive oxygen species (ROS) generation with inductions in Nrf2-antioxidant signaling. Moreover, Q3G treatment repressed Nrf2 ubiquitination, and enhanced the association of Keap1 and p62 in the LPS-treated cells. Q3G also showed potential in inducing autophagy, as demonstrated by formation of acidic vesicular organelles (AVOs) and upregulation of autophagy factors. Next, the autolysosomes formation and cell survival were decreased by Q3G under pre-treatment with a lysosome inhibitor, chloroquine (CQ). Furthermore, mechanistic assays indicated that anti-pulmonary injury effects of Q3G might be mediated via Nrf2 signaling, as confirmed by the transfection of Nrf2 siRNA. Finally, Q3G significantly alleviated the development of pulmonary injury in vivo, which may result from inhibiting the LPS-induced lung dysfunction and edema. These findings emphasize a toxicological perspective, providing new insights into the mechanisms of Q3G's protective effects on LPS-induced pulmonary injury and highlighting its role in dual activating Nrf2 and autophagy pathways.

Lung ultrasonography versus chest CT for assessing peripheric pulmonary lesions in hemorrhagic fever with renal syndrome: a prospective comparative study in China.

OBJECTIVES: To compare the performances of lung ultrasonography (LUS) versus chest CT for assessing peripheric pulmonary lesions in hemorrhagic fever with renal syndrome (HFRS). METHODS: Paired LUS and chest CT scan were prospectively performed and compared when in diagnosing five pathologies including region with alveolar-interstitial pattern (RAIP), alveolar-interstitial syndrome (AIS), lung consolidation, pleural effusion (PE), and pericardial effusion, in each patient with HFRS. RESULTS: Forty-four patients (aged 39.9 ± 15.0 years, 35 males) were included, from which 68 paired LUS and chest CT imaging data of 816 lung regions were obtained and analyzed. Compared with chest CT, LUS showed high sensitivity (92.19-100%) and negative predictive value (95.9-100%), but relatively low specificity (39.47-97.21%) and positive predictive value (37.5-76.47%) for diagnosing the above pathologies. McNemer's test showed LUS detected more positive findings than chest CT (all p ≤ 0.002). There was a strong correlation between LUS and chest CT scores (rs = 0.7141, p < 0.0001) and both scores correlated with the disease severity, hospital days, and partial laboratory profiles in HFRS patients. CONCLUSIONS: LUS was comparable with chest CT for diagnosing peripheric pulmonary lesions and clinical assessment in patients with HFRS. Given the high sensitivity and negative predictive value compared with chest CT, LUS can be used as an excellent rule-out tool in HFRS, while its use in rule-in still requires more evidence. Considering the obvious advantages of LUS being a bedside, less expansive, and non-radiating exam, future multi-center randomized LUS versus chest CT studies may help to guide the preferred method. KEY POINTS: • LUS could detect more positive findings than chest CT in assessing peripheric pulmonary lesions in patients with hemorrhagic fever with renal syndrome (HFRS). • Compared with chest CT, LUS showed high sensitivity but relatively low specificity when diagnosing the peripheric pulmonary lesions caused by HFRS. • Both LUS and chest CT scores correlated with the disease severity, hospital days, and partial laboratory profiles in HFRS.

Lias overexpression alleviates pulmonary injury induced by fine particulate matter in mice.

Oxidative stress and inflammation are mechanisms underlying toxicity induced by fine particulate matter (PM2.5). The antioxidant baseline of the human body modulates the intensity of oxidative stress in vivo. This present study aimed to evaluate the role of endogenous antioxidants in alleviating PM2.5-induced pulmonary injury using a novel mouse model (LiasH/H) with an endogenous antioxidant capacity of approximately 150% of its wild-type counterpart (Lias+/+). LiasH/H and wild-type (Lias+/+) mice were randomly divided into control and PM2.5 exposure groups (n = 10), respectively. Mice in the PM2.5 group and the control group were intratracheally instilled with PM2.5 suspension and saline, respectively, once a day for 7 consecutive days. The metal content, major pathological changes in the lung, and levels of oxidative stress and inflammation biomarkers were examined. The results showed that PM2.5 exposure induced oxidative stress in mice. Overexpression of the Lias gene significantly increased the antioxidant levels and decreased inflammatory responses induced by PM2.5. Further study found that LiasH/H mice exerted their antioxidant function by activating the ROS-p38MAPK-Nrf2 pathway. Therefore, the novel mouse model is useful for the elucidation of the mechanisms of pulmonary injury induced by PM2.5.

Exploring the potential neurotoxicity of vaping vitamin E or vitamin E acetate.

Serious adverse health effects have been reported with the use of vaping products, including neurologic disorders and e-cigarette or vaping product use-associated lung injury (EVALI). Vitamin E acetate, likely added as a diluent to cannabis-containing products, was linked to EVALI. Literature searches were performed on vitamin E and vitamin E acetate-associated neurotoxicity. Blood brain barrier (BBB) penetration potential of vitamin E and vitamin E acetate were evaluated using cheminformatic techniques. Review of the literature showed that the neurotoxic potential of inhalation exposures to these compounds in humans is unknown. Physico-chemical properties demonstrate these compounds are lipophilic, and molecular weights indicate vitamin E and vitamin E acetate have the potential for BBB permeability. Computational models also predict both compounds may cross the BBB via passive diffusion. Based on literature search, no experimental nonclinical studies and clinical information on the neurotoxic potential of vitamin E via inhalation. Neurotoxic effects from pyrolysis by-product, phenyl acetate, structurally analogous to vitamin E acetate, suggests vitamin E acetate has potential for central nervous system (CNS) impairment. Cheminformatic model predictions provide a theoretical basis for potential CNS permeability of these inhaled dietary ingredients suggesting prioritization to evaluate for potential hazard to the CNS.

Successful treatment of pulmonary injury due to nitrogen oxide exposure with extracorporeal membrane oxygenation: a report of two cases and literature review.

Background: Severe nitrogen oxide poisoning can lead to life-threatening pulmonary injury.Methods: we report two cases of severe nitrogen-oxide-induced hypoxia treated with veno-venous extracorporeal membrane oxygenation (ECMO). After exposure, the conditions of both patients continued to deteriorate despite maximal mechanical ventilation with a fraction of inspired oxygen of 100%; therefore, we started veno-venous ECMO. The times from presentation to the initiation of ECMO in the two patients were 1 and 2 days. The hypoxemia and respiratory failure improved quickly after ECMO support.Results: The patients were discharged without complications. The durations of ECMO for the two patients were 5 and 6 days. Conclusion: This report describes how early ECMO support was used to treat potentially fatal pulmonary injury after exposure to nitrogen oxide. The duration of the ECMO run is a critical determinant of patient survival.

Lycopene hampers lung injury due to skeletal muscle ischemia-reperfusion in rat model.

This study investigates lycopene's preventive efficacy in skeletal muscle ischemia-reperfusion (I/R) induced lung injury. Thirty-two rats were randomly assigned to control group, lycopene group, I/R group and I/R + lycopene group. In the lycopene and I/R + lycopene groups, the rats initially received 10 mg/kg/day lycopene orally for 15 days. Then, dissection around the abdominal aorta was performed in all rats under general anesthesia. The aorta was clamped at the infrarenal level in the I/R group and I/R + lycopene group for two hours before two hours of reperfusion. The mean serum levels of malondialdehyde (53.0 ± 20.14 nmol/mL) and superoxide dismutase (1.03 ± 0.16 U/mL) were higher and lower in the I/R group than the other three groups, respectively (p < 0.001). The mean serum IMA level of I/R + lycopene group (0.42 ± 0.04 abs/u) was lower than the I/R group (0.47 ± 0.04 abs/u) (p = 0.015). The mean tissue malondialdehyde levels of I/R group (69.10 ± 11.55 nmol/mL) and I/R + lycopene group (68.36 ± 21.17 nmol/mL) were high compared to the control group (49.87 ± 6.52 nmol/mL) and lycopene group (47.82 ± 4.44 nmol/mL) (p = 0.002). The mean tissue glutathione peroxidase (p < 0.001) and superoxide dismutase (p = 0.001) levels of I/R group (121.81 ± 43.59 nmol/mL and 25.17 ± 8.69 U/mL) were low compared to the control group (236.12 ± 18.01 nmol/mL and 46.30 ± 5.17 U/mL), lycopene group (227.52 ± 16.92 nmol/mL and 45.82 ± 4.02 U/mL), and I/R + lycopene group (176.02 ± 24.27 nmol/mL and 35.20 ± 4.85 U/mL). The histopathological analyses of I/R + lycopene group indicated less significant changes than the control group. Tissue damage in the I/R + lycopene group was less prominent than the I/R group. These findings suggest oral lycopene supplementation as a promising prevention against skeletal muscle I/R caused lung injury.

Risk stratification by long non-coding RNAs profiling in COVID-19 patients.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic worldwide. Long non-coding RNAs (lncRNAs) are a subclass of endogenous, non-protein-coding RNA, which lacks an open reading frame and is more than 200 nucleotides in length. However, the functions for lncRNAs in COVID-19 have not been unravelled. The present study aimed at identifying the related lncRNAs based on RNA sequencing of peripheral blood mononuclear cells from patients with SARS-CoV-2 infection as well as health individuals. Overall, 17 severe, 12 non-severe patients and 10 healthy controls were enrolled in this study. Firstly, we reported some altered lncRNAs between severe, non-severe COVID-19 patients and healthy controls. Next, we developed a 7-lncRNA panel with a good differential ability between severe and non-severe COVID-19 patients using least absolute shrinkage and selection operator regression. Finally, we observed that COVID-19 is a heterogeneous disease among which severe COVID-19 patients have two subtypes with similar risk score and immune score based on lncRNA panel using iCluster algorithm. As the roles of lncRNAs in COVID-19 have not yet been fully identified and understood, our analysis should provide valuable resource and information for the future studies.

Autophagy, TERT, and mitochondrial dysfunction in hyperoxia.

Ventilation with gases containing enhanced fractions of oxygen is the cornerstone of therapy for patients with hypoxia and acute respiratory distress syndrome. Yet, hyperoxia treatment increases free reactive oxygen species (ROS)-induced lung injury, which is reported to disrupt autophagy/mitophagy. Altered extranuclear activity of the catalytic subunit of telomerase, telomerase reverse transcriptase (TERT), plays a protective role in ROS injury and autophagy in the systemic and coronary endothelium. We investigated interactions between autophagy/mitophagy and TERT that contribute to mitochondrial dysfunction and pulmonary injury in cultured rat lung microvascular endothelial cells (RLMVECs) exposed in vitro, and rat lungs exposed in vivo to hyperoxia for 48 h. Hyperoxia-induced mitochondrial damage in rat lungs [TOMM20, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)], which was paralleled by increased markers of inflammation [myeloperoxidase (MPO), IL-1ß, TLR9], impaired autophagy signaling (Beclin-1, LC3B-II/1, and p62), and decreased the expression of TERT. Mitochondrial-specific autophagy (mitophagy) was not altered, as hyperoxia increased expression of Pink1 but not Parkin. Hyperoxia-induced mitochondrial damage (TOMM20) was more pronounced in rats that lack the catalytic subunit of TERT and resulted in a reduction in cellular proliferation rather than cell death in RLMVECs. Activation of TERT or autophagy individually offset mitochondrial damage (MTT). Combined activation/inhibition failed to alleviate hyperoxic-induced mitochondrial damage in vitro, whereas activation of autophagy in vivo decreased mitochondrial damage (MTT) in both wild type (WT) and rats lacking TERT. Functionally, activation of either TERT or autophagy preserved transendothelial membrane resistance. Altogether, these observations show that activation of autophagy/mitophagy and/or TERT mitigate loss of mitochondrial function and barrier integrity in hyperoxia.NEW & NOTEWORTHY In cultured pulmonary artery endothelial cells and in lungs exposed in vivo to hyperoxia, autophagy is activated, but clearance of autophagosomes is impaired in a manner that suggests cross talk between TERT and autophagy. Stimulation of autophagy prevents hyperoxia-induced decreases in mitochondrial metabolism and sustains monolayer resistance. Hyperoxia increases mitochondrial outer membrane (TOMM20) protein, decreases mitochondrial function, and reduces cellular proliferation without increasing cell death.

Pulmonary and vascular effects of acute ozone exposure in diabetic rats fed an atherogenic diet.

Air pollutants may increase risk for cardiopulmonary disease, particularly in susceptible populations with metabolic stressors such as diabetes and unhealthy diet. We investigated effects of inhaled ozone exposure and high-cholesterol diet (HCD) in healthy Wistar and Wistar-derived Goto-Kakizaki (GK) rats, a non-obese model of type 2 diabetes. Male rats (4-week old) were fed normal diet (ND) or HCD for 12 weeks and then exposed to filtered air or 1.0 ppm ozone (6 h/day) for 1 or 2 days. We examined pulmonary, vascular, hematology, and inflammatory responses after each exposure plus an 18-h recovery period. In both strains, ozone induced acute bronchiolar epithelial necrosis and inflammation on histopathology and pulmonary protein leakage and neutrophilia; the protein leakage was more rapid and persistent in GK compared to Wistar rats. Ozone also decreased lymphocytes after day 1 in both strains consuming ND (~50%), while HCD increased circulating leukocytes. Ozone increased plasma thrombin/antithrombin complexes and platelet disaggregation in Wistar rats on HCD and exacerbated diet effects on serum IFN-γ, IL-6, KC-GRO, IL-13, and TNF-α, which were higher with HCD (Wistar>GK). Ex vivo aortic contractility to phenylephrine was lower in GK versus Wistar rats at baseline(~30%); ozone enhanced this effect in Wistar rats on ND. GK rats on HCD had higher aortic e-NOS and tPA expression compared to Wistar rats. Ozone increased e-NOS in GK rats on ND (~3-fold) and Wistar rats on HCD (~2-fold). These findings demonstrate ways in which underlying diabetes and HCD may exacerbate pulmonary, systemic, and vascular effects of inhaled pollutants.

Longitudinal clinical and radiographic evaluation reveals interleukin-6 as an indicator of persistent pulmonary injury in COVID-19.

Rationale: Previous studies of coronavirus disease 2019 (COVID-19) were mainly focused on cross-sectional analysis. In this study, we sought to evaluate the dynamic changes of immunological and radiographic features, and the association with the outcome of pulmonary lesions in COVID-19 patients. Methods: Peripheral blood samples and radiographic data were collected longitudinally for up to 8 weeks from 158 laboratory-confirmed COVID-19 patients. The chest computed tomography (CT) scans were scored based on a semi-quantification assessment according to the extent of pulmonary abnormalities; the temporal change of the immunological and radiographic features was analyzed. Results: Compared with mild and moderate patients, severe patients had significantly decreased counts of lymphocytes, CD4+ T cells, CD8+ T cells, and CD19+ B cells but dramatically elevated counts of neutrophils and levels of interleukin (IL)-6. Sequential monitoring showed a sustained increase in lymphocytes counts and significantly decreased levels of IL-6 in severe patients during the disease course. Notably, patients with persistent pulmonary lesions (CT score ≥ 5 in week 8) showed high levels of IL-6 during the follow-up period, compared with those with recovery lesions (CT score < 5 in week 8). More importantly, the peak expression of IL-6 prior to the aggravated lung injury was mainly found in patients with persistent lesions, and multivariate analysis showed that IL-6 level upon admission was an independent factor associated with the persistent pulmonary injury. Conclusion: Prolonged elevation of IL-6 is associated with persistent pulmonary lesions in COVID-19 patients. Sequential monitoring and timely intervention of IL-6 may favor the clinical management of COVID-19.

Lung Injury After Neonatal Congenital Cardiac Surgery Is Mild and Modifiable by Corticosteroids.

OBJECTIVES: The present study was performed to determine whether lung injury manifests as lung edema in neonates after congenital cardiac surgery and whether a stress-dose corticosteroid (SDC) regimen attenuates postoperative lung injury in neonates after congenital cardiac surgery. DESIGN: A supplementary report of a randomized, double-blinded, placebo-controlled clinical trial. SETTING: A pediatric tertiary university hospital. PARTICIPANTS: Forty neonates (age ≤28 days) undergoing congenital cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: After anesthesia induction, patients were assigned randomly to receive intravenously either 2 mg/kg methylprednisolone or placebo b, which was followed by hydrocortisone or placebo bolus six hours after weaning from CPB for five days as follows: 0.2 mg/kg/h for 48 hours, 0.1 mg/kg/h for the next 48 hours, and 0.05 mg/kg/h for the following 24 hours. MEASUREMENTS AND MAIN RESULTS: The chest radiography lung edema score was lower in the SDC than in the placebo group on the first postoperative day (POD one) (p = 0.03) and on PODs two and three (p = 0.03). Furthermore, a modest increase in the edema score of 0.9 was noted in the placebo group, whereas the edema score remained at the preoperative level in the SDC group. Postoperative dynamic respiratory system compliance was higher in the SDC group until POD three (p < 0.01). However, postoperative oxygenation; length of mechanical ventilation; and tracheal aspirate biomarkers of inflammation and oxidative stress, namely interleukin-6, interleukin-8, resistin, and 8-isoprostane, showed no differences between the groups. CONCLUSIONS: The SDC regimen reduced the development of mild and likely clinically insignificant radiographic lung edema and improved postoperative dynamic respiratory system compliance without adverse events, but it failed to improve postoperative oxygenation and length of mechanical ventilation.

Protective and anti-inflammatory effect of selenium nano-particles against bleomycin-induced pulmonary injury in male rats.

Pulmonary fibrosis (PF) is an interstitial lung disease, in which the exact pathologic mechanisms are not fully understood. Drug trials for the treatment of PF have shown disappointing results and controversial. Recently, selenium nanoparticles (SeNPs) have received great attention for potential use in treatments, due to high bioactivity features and lower toxicity. This study evaluated the protective effect of SeNPs against pulmonary injury induced by bleomycin (single dose, 4 mg/kg, intratracheal) in male rats in early and late phases of the disease. The rats were treated with SeNPs by intraperitoneal injection (0.5 mg SeNP/kg) for five consecutive days in the early phase (a day after injection of bleomycin) and late phase (a week after injection of bleomycin). The results showed that injection of SeNPs in the early phase improved the degree of alveolitis and inflammation and lung structure damage. Also, led to significant decreases in density of transforming growth factor- ß1 (TGF-ß1) in the lung and tumor necrosis factor-α (TNF-α) levels in the serum and lung homogenates compared with bleomycin-administrated group. Notably, treatment with the SeNP during the late phase did not show any ameliorative effects. Thus, the data suggest that SeNP has a protective effect against bleomycin-induced pulmonary injury in rats in the early phase of the disease. This might mean that SeNPs may be a new therapeutic agent for the improvement of this disease in the early phases.

Caloric restriction attenuates C57BL/6 J mouse lung injury and extra-pulmonary toxicity induced by real ambient particulate matter exposure.

BACKGROUND: Caloric restriction (CR) is known to improve health and extend lifespan in human beings. The effects of CR on adverse health outcomes in response to particulate matter (PM) exposure and the underlying mechanisms have yet to be defined. RESULTS: Male C57BL/6 J mice were fed with a CR diet or ad libitum (AL) and exposed to PM for 4 weeks in a real-ambient PM exposure system located at Shijiazhuang, China, with a daily mean concentration (95.77 µg/m3) of PM2.5. Compared to AL-fed mice, CR-fed mice showed attenuated PM-induced pulmonary injury and extra-pulmonary toxicity characterized by reduction in oxidative stress, DNA damage and inflammation. RNA sequence analysis revealed that several pulmonary pathways that were involved in production of reactive oxygen species (ROS), cytokine production, and inflammatory cell activation were inactivated, while those mediating antioxidant generation and DNA repair were activated in CR-fed mice upon PM exposure. In addition, transcriptome analysis of murine livers revealed that CR led to induction of xenobiotic metabolism and detoxification pathways, corroborated by increased levels of urinary metabolites of polycyclic aromatic hydrocarbons (PAHs) and decreased cytotoxicity measured in an ex vivo assay. CONCLUSION: These novel results demonstrate, for the first time, that CR in mice confers resistance against pulmonary injuries and extra-pulmonary toxicity induced by PM exposure. CR led to activation of xenobiotic metabolism and enhanced detoxification of PM-bound chemicals. These findings provide evidence that dietary intervention may afford therapeutic means to reduce the health risk associated with PM exposure.

Effect of ulinastatin on interleukins and pulmonary function in bypass patients: a meta-analysis of randomized controlled trials.

BACKGROUND: Our aim was to evaluate the effect of urinary trypsin inhibitors (UTI) on interleukin, tumor necrosis factor-α (TNF-α), and polymorphonuclear neutrophil elastase (PMNE) levels as well as on pulmonary function in patients undergoing cardiopulmonary bypass. MATERIALS AND METHODS: We searched the following databases for relevant studies: PubMed, Medline (Ovid SP), Cochrane Library, Wanfang Data, China Biology Medicine Database, Chinese Periodical Database, China Knowledge Resource Integrated Database, and Chinese Clinical Trial Registry. Two investigators independently collected the data and assessed the quality of each study. RevMan 5.3 was used for the meta-analysis. RESULTS: In total, 15 randomized controlled trials (646 patients) met the inclusion criteria. There was a significant decrease in TNF-α, interleukin-6 (IL-6), IL-8, and PMNE levels at 6 h and 24 h after UTI treatment and an increase in IL-10 levels; additionally, there was a decrease in respiratory index and an improvement in the oxygenation index. Nevertheless, UTI treatment did not affect the length of intensive care unit stay, alveolar-arterial oxygen partial pressure difference, adverse lung events, or hospital mortality. Because of the high heterogeneity of the included trials, the results should be assessed carefully. CONCLUSION: UTI treatment can suppress proinflammatory cytokine elevation and upregulate the release of anti-inflammatory mediators, thereby reducing pulmonary injury and improving pulmonary function after cardiopulmonary bypass.

Polyethylene Glycol 35 (PEG35) Protects against Inflammation in Experimental Acute Necrotizing Pancreatitis and Associated Lung Injury.

Acute pancreatitis is an inflammatory disorder of the pancreas. Its presentation ranges from self-limiting disease to acute necrotizing pancreatitis (ANP) with multiorgan failure and a high mortality. Polyethylene glycols (PEGs) are non-immunogenic, non-toxic, and water-soluble chemicals composed of repeating units of ethylene glycol. The present article explores the effect of PEG35 administration on reducing the severity of ANP and associated lung injury. ANP was induced by injection of 5% sodium taurocholate into the biliopancreatic duct. PEG35 was administered intravenously either prophylactically or therapeutically. Three hours after ANP induction, pancreas and lung tissue samples and blood were collected and ANP severity was assessed. To evaluate the inflammatory response, gene expression of pro-inflammatory cytokines and chemokine and the changes in the presence of myeloperoxidase and adhesion molecule levels were determined in both the pancreas and the lung. To evaluate cell death, lactate dehydrogenase (LDH) activity and apoptotic cleaved caspase-3 localization were determined in plasma and in both the pancreatic and lung tissue respectively. ANP-associated local and systemic inflammatory processes were reduced when PEG35 was administered prophylactically. PEG35 pre-treatment also protected against acute pancreatitis-associated cell death. Notably, the therapeutic administration of PEG35 significantly decreased associated lung injury, even when the pancreatic lesion was equivalent to that in the untreated ANP-induced group. Our results support a protective role of PEG35 against the ANP-associated inflammatory process and identify PEG35 as a promising tool for the treatment of the potentially lethal complications of the disease.

Protective anti-inflammatory activity of tovophyllin A against acute lung injury and its potential cytotoxicity to epithelial lung and breast carcinomas.

Tovophyllin A (TA) is a xanthone isolated from Garcinia mangostana L. (GM, Guttiferae) pericarps that possesses various beneficial bioactivities. However, its protective effects on acute lung injury (ALI) and lung carcinoma have not yet been explored. The current work was designed to investigate the protective potential of TA against ALI and explore the possible mechanism of action. Two different doses of TA were tested against lipopolysaccharide (LPS)-induced ALI in mice. Moreover, the cytotoxic potential of TA was assessed in epithelial lung (A549 cells) and breast (MCF7 cells) carcinomas utilizing a sulforhodamine B (SRB) assay. The results revealed that TA possessed the ability to protect against LPS-induced acute lung damage. TA attenuated LPS-induced pulmonary edema, as it lowered the protein content in the bronchoalveolar lavage fluid (BALF) and the lung W/D ratio. In addition, TA counteracted inflammatory cell infiltration into the lung tissue, as shown by the total and differential cell counts in the BALF and histopathological examination of the lungs. The oxidative burden in the pulmonary tissue was ameliorated in TA-treated animals as there were reductions in the malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) levels in the lung tissue. TA increased the levels of antioxidants such as reduced glutathione (GSH) and superoxide dismutase (SOD) in the lungs. Furthermore, TA inhibited the activation of nuclear factor-κB (NF-κB). In addition, TA had potent anti-inflammatory activity as it reduced the immunoexpression and levels of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß and IL-6. Furthermore, TA showed significantly enhanced cytotoxic activity against the MCF-7 and A549 cell lines with IC50s of 6.1 and 2.2 µM, respectively, compared to doxorubicin (IC50s of 0.41 and 0.74 µM, respectively). In conclusion, TA ameliorates LPS-induced ALI through the suppression of oxidative stress and inflammation. These findings suggest the potential use of this compound as a future treatment for ALI.

[The differential diagnosis of pulmonary infiltrates in cancer patients during the outbreak of the 2019 novel coronavirus disease].

Objective: To investigate the principles of differential diagnosis of pulmonary infiltrates in cancer patients during the outbreak of novel coronavirus (2019-nCoV) by analyzing one case of lymphoma who presented pulmonary ground-glass opacities (GGO) after courses of chemotherapy. Methods: Baseline demographics and clinicopathological data of eligible patients were retrieved from medical records. Information of clinical manifestations, history of epidemiology, lab tests and chest CT scan images of visiting patients from February 13 to February 28 were collected. Literatures about pulmonary infiltrates in cancer patients were searched from databases including PUBMED, EMBASE and CNKI. Results: Among the 139 cancer patients who underwent chest CT scans before chemotherapy, pulmonary infiltrates were identified in eight patients (5.8%), five of whom were characterized with GGOs in lungs. 2019-nCoV nuclear acid testing was performed in three patients and the results were negative. One case was a 66-year-old man who was diagnosed with non-Hodgkin lymphoma and underwent CHOP chemotherapy regimen. His chest CT scan image displayed multiple GGOs in lungs and the complete blood count showed decreased lymphocytes. This patient denied any contact with confirmed/suspected cases of 2019-nCoV infection, fever or other respiratory symptoms. Considering the negative result of nuclear acid testing, this patient was presumptively diagnosed with viral pneumonia and an experiential anti-infection treatment had been prescribed for him. Conclusions: The 2019 novel coronavirus disease (COVID-19) complicates the clinical scenario of pulmonary infiltrates in cancer patients. The epidemic history, clinical manifestation, CT scan image and lab test should be taken into combined consideration. The 2019-nCoV nuclear acid testing might be applied in more selected patients. Active anti-infection treatment and surveillance of patient condition should be initiated if infectious disease is considered.

Reduning injection ameliorates paraquat-induced acute lung injury by regulating AMPK/MAPK/NF-κB signaling.

Reduning injection (RDN), a patented Chinese medicine, is broadly used for common cold and lung infection in clinic, but the mechanism underlying its effects on inflammation-related pulmonary injury remains unclear. Paraquat (PQ, bolus 15 mg/kg dose, ip) was administered for acute lung injury induction in mice, which were orally administered dexamethasone (2 mg/kg) or RDN (50 and 100 mg/kg/day) for 5 days. After treatment, plasma and lung tissue samples from the euthanized animals were obtained and analyzed by histological, biochemical and immunoblot assays. Histological observation demonstrated RDN alleviated PQ-induced lung damage. Meanwhile, RDN suppressed myeloperoxidase (MPO) activity, reduced the wet/dry (W/D) ratio and decreased the amounts of total leukocytes and neutrophils. Treatment also markedly decreased the amounts of malondialdehyde, MPO, and inflammatory cytokines while increasing superoxide dismutase activity in comparison with the PQ group. In immunoblot, RDN blocked the phosphorylation levels of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), JNK, ERK, p38, inhibitor of nuclear factor κB kinase and nuclear factor-κB (NF-κB) in lung tissue specimens in PQ-challenged animals, which was further verified in vitro. The above data indicated protective effects for RDN in PQ-induced lung damage, possibly through inhibition of the AMPK/MAPK/NF-κB pathway.

Effects of Breath-Hold Deep Diving on the Pulmonary System.

This short review focuses on pulmonary injury in breath-hold (BH) divers. When practicing their extreme leisure sport, they are exposed to increased pressure on pulmonary gas volumes, hypoxia, and increased partial gas pressures. Increasing ambient pressures do present a serious problem to BH deep divers, because the semi-rigid thorax prevents the deformation required by the Boyle-Mariotte law. As a result, a negative-pressure barotrauma (lung squeeze) with acute hemoptysis is not uncommon. Respiratory maneuvers such as glossopharyngeal insufflation (GI) and glossopharyngeal exsufflation (GE) are practiced to prevent lung squeeze and to permit equalizing the paranasal sinuses and the middle ear. GI not only impairs venous return, thereby provoking hypotension and even fainting, but also produces intrathoracic pressures likely to induce pulmonary barotrauma that is speculated to induce long-term injury. GE, in turn, further increases the already negative intrapulmonary pressure, thereby favoring alveolar collapse (atelectasis). Finally, hypoxia seemingly not only induces brain injury but initiates the opening of intrapulmonary shunts. These pathways are large enough to permit transpulmonary passage of venous N2 bubbles, making stroke-like phenomena in deep BH divers possible.