Lung Injury
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2021 ◽  
Jinju Li ◽  
Rongge Shao ◽  
Qiuwen Xie ◽  
XueKe Du

Abstract Purpose:Ulinastatin (UTI) is an endogenous protease inhibitor with potent anti-inflammatory, antioxidant and organ protective effects. The inhibitor has been reported to ameliorate inflammatory lung injury but precise mechanisms remain unclear. Methods: An in vivo model of lung injury has been constructed by intratracheal infusion of lipopolysaccharide (LPS). The number of neutrophils and the phagocytosis of apoptotic neutrophils were observed by Diff- Quick method. Lung injury was observed by HE staining .BALF cells were counted by hemocytometer and concentrations of protein plus inflammatory factors were measured with a BCA test kit. During in vitro experiments, RAW264.7 cells were pretreated with UTI (1000 and 5000U/ mL), stained with CellTrackerTM Green B0DIPYTM and HL60 cells added with UV-induced apoptosis and PKH26 Red staining. The expression of ERK5\Mer related proteins was detected by western blot and immunofluorescence.Results: An in vivo model of lung injury has been constructed by intratracheal infusion of lipopolysaccharide (LPS). UTI treatment enhanced the phagocytotic effect of mouse alveolar macrophages on neutrophils, alleviated lung lesions, decreased the pro-inflammatory factor and total protein content of BALF and increased levels of anti-inflammatory factors. in vitro experiments ,UTI enhanced the phagocytosis of apoptotic bodies by RAW264.7 cells in a dose-dependent manner. Increased expression levels of ERK5 and Mer by UTI were shown by Western blotting and immunofluorescence.Conclusions: UTI mediated the activation of the ERK5/Mer signaling pathway, enhanced phagocytosis of neutrophils by macrophages and improved lung inflammation. The current study indicates potential new clinical approaches for accelerating the recovery from lung inflammation.

2021 ◽  
Mei-Chuan Chen ◽  
Kevin Shu-Leung Lai ◽  
Ko-Ling Chien ◽  
Sing-Teck Teng ◽  
Yuh-Rong Lin ◽  

Abstract Background:The novel coronavirus disease 2019 (COVID-19) has been a global pandemic health issue since 30, January, 2020. Mortality rate was as high as more than 50% in critically ill patients. The Stem cell treatment is effective in refractory severe critically ill COVID-19 patients, but immune regulation mechanisms have not been reported well. Therefore, we evaluate the clinical efficacy and immune modulation of placenta-derived mesenchymal stem cells (pcMSCs) (MatriPlax) in severe critically ill COVID-19 infection who are refractory to current standard therapies.Methods:Intravenous infusion of 1 × 107 MatriPlax was given to five severe COVID-19 patients at Day 0 and day 4. Serum inflammatory markers and immune profiles were studied at Day 0, 4 and 8. Clinical parameters and 28-days mortality were compared between treated group and control group.Results:The treatment group had no 28-days mortality and Murray’s lung injury score was significantly improved compared with control group. After treatment, Ferritin, C-reactive protein (CRP) and Lactate dehydrogenases (LDH) were significantly reduced and lymphopenia was improved. IL-6, IL-1β, IFN-γ and IL-2 were significantly decreased together with decrease in IL-10 reflecting decreasing intensity of inflammation. Immune cell profiles showed increase in CD4+ T cells (CD4+ naïve T cells, CD4+ memory T cells subtypes), Treg cells, CD19+ B cells (and CD19+ naive B cells, CD27+ switched B cells subtypes) and dendritic cells, and a significant decrease in CD14+ monocytes (and CD16- classical, CD16+ non-classical subtypes) monocytes as well as plasma/plasmablast cells. pc-MSCs treatment suppressed hyper-inflammatory states of innate immune responses to COVID-19 infection by increasing Treg cells, decreasing monocytes and plasma/plasmablast cells, and promoted CD4+ T cells and CD19+ B cells towards adaptive immune responses.Conclusion:The intravenous transplantation of Matriplax was safe and effective for severe critically ill COVID-19 patients, especially those who were refractory to current standard care and immunosuppressive therapies

Yong Zhao ◽  
Hao Zheng ◽  
Shengnan Yang ◽  
Xiaoqing Zhang ◽  
Weigang Dong ◽  

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1913
Ahmed Elsaie ◽  
Renuka T. Menon ◽  
Amrit K. Shrestha ◽  
Sharada H. Gowda ◽  
Nidhy P. Varghese ◽  

Bronchopulmonary dysplasia and pulmonary hypertension, or BPD-PH, are serious chronic lung disorders of prematurity, without curative therapies. Hyperoxia, a known causative factor of BPD-PH, activates adenosine monophosphate-activated protein kinase (AMPK) α1 in neonatal murine lungs; however, whether this phenomenon potentiates or mitigates lung injury is unclear. Thus, we hypothesized that (1) endothelial AMPKα1 is necessary to protect neonatal mice against hyperoxia-induced BPD-PH, and (2) AMPKα1 knockdown decreases angiogenesis in hyperoxia-exposed neonatal human pulmonary microvascular endothelial cells (HPMECs). We performed lung morphometric and echocardiographic studies on postnatal day (P) 28 on endothelial AMPKα1-sufficient and -deficient mice exposed to 21% O2 (normoxia) or 70% O2 (hyperoxia) from P1–P14. We also performed tubule formation assays on control- or AMPKα1-siRNA transfected HPMECs, exposed to 21% O2 or 70% O2 for 48 h. Hyperoxia-mediated alveolar and pulmonary vascular simplification, pulmonary vascular remodeling, and PH were significantly amplified in endothelial AMPKα1-deficient mice. AMPKα1 siRNA knocked down AMPKα1 expression in HPMECs, and decreased their ability to form tubules in normoxia and hyperoxia. Furthermore, AMPKα1 knockdown decreased proliferating cell nuclear antigen expression in hyperoxic conditions. Our results indicate that AMPKα1 is required to reduce hyperoxia-induced BPD-PH burden in neonatal mice, and promotes angiogenesis in HPMECs to limit lung injury.

2021 ◽  
Vol 16 (1) ◽  
Yuhan Liu ◽  
Jiabin Zhou ◽  
Yingying Luo ◽  
Jinxiao Li ◽  
Luorui Shang ◽  

Abstract Background Honokiol (HKL) has been reported to ameliorate lipopolysaccharide (LPS)-induced acute lung injury (ALI). However, its potential mechanism of its protective effects remains unclear. In this study, the protective mechanism of HKL on LPS-induced ALI was explored in vivo and in vitro. Methods In vivo, the SD rats were intratracheally instilled with LPS (5 mg/kg) to establish an acute lung injury model and then treated with HKL (1.25/2.5/5 mg/kg) or ML385 (30 mg/kg) intraperitoneally. In vitro, the human bronchial epithelial cell line (BEAS-2B) was stimulated with LPS and ATP to induce pyroptosis and treated with HKL (12.5/25/50 μM). Small interfering RNA (siRNA) technique was used to knockdown Nrf2 in BEAS-2B cells. The protein and mRNA expression levels of Nrf2, HO-1, NLRP3, ASC, CASP1, and GSDMD in cells and lung tissues were detected by western blot and real time-PCR. The expression levels of interleukin (IL)-1β, IL-18, MPO, MDA, and SOD in bronchoalveolar lavage fluid (BALF) and supernatant were determined by ELISA. The degree of pathological injury of lung tissue was evaluated by H&E staining. Results The results showed that HKL could alleviate oxidative stress and inflammatory responses by regulating the levels of MPO, MDA, SOD, IL-1β, IL-18 in supernatant. And it could also inhibit the expression levels of NLRP3, ASC, CASP1, GSDMD via activation of Nrf2 in BEAS-2B cells. Further studies revealed that HKL could attenuate the pathological injury in LPS-induced ALI rats, and the molecular mechanism was consistent with the results in vitro. Conclusions Our study demonstrated that HKL could alleviate LPS-induced ALI by reducing the oxidative stress and inhibiting NLRP3 inflammasome-mediated pyroptosis, which was partly dependent on the Nrf2 activation. Graphical Abstract

2021 ◽  
Arindam Chakrabarti ◽  
Allen Nguyen ◽  
Margaret M. Newhams ◽  
Maikke B. Ohlson ◽  
Xiaoying Yang ◽  

Critical Care ◽  
2021 ◽  
Vol 25 (1) ◽  
Masaaki Sakuraya ◽  
Hiromu Okano ◽  
Tomoyuki Masuyama ◽  
Shunsuke Kimata ◽  
Satoshi Hokari

Abstract Background Although non-invasive respiratory management strategies have been implemented to avoid intubation, patients with de novo acute hypoxaemic respiratory failure (AHRF) are high risk of treatment failure. In the previous meta-analyses, the effect of non-invasive ventilation was not evaluated according to ventilation modes in those patients. Furthermore, no meta-analyses comparing non-invasive respiratory management strategies with invasive mechanical ventilation (IMV) have been reported. We performed a network meta-analysis to compare the efficacy of non-invasive ventilation according to ventilation modes with high-flow nasal oxygen (HFNO), standard oxygen therapy (SOT), and IMV in adult patients with AHRF. Methods The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and Ichushi databases were searched. Studies including adults with AHRF and randomized controlled trials (RCTs) comparing two different respiratory management strategies (continuous positive airway pressure (CPAP), pressure support ventilation (PSV), HFNO, SOT, or IMV) were reviewed. Results We included 25 RCTs (3,302 participants: 27 comparisons). Using SOT as the reference, CPAP (risk ratio [RR] 0.55; 95% confidence interval [CI] 0.31–0.95; very low certainty) was associated significantly with a lower risk of mortality. Compared with SOT, PSV (RR 0.81; 95% CI 0.62–1.06; low certainty) and HFNO (RR 0.90; 95% CI 0.65–1.25; very low certainty) were not associated with a significantly lower risk of mortality. Compared with IMV, no non-invasive respiratory management was associated with a significantly lower risk of mortality, although all certainties of evidence were very low. The probability of being best in reducing short-term mortality among all possible interventions was higher for CPAP, followed by PSV and HFNO; IMV and SOT were tied for the worst (surface under the cumulative ranking curve value: 93.2, 65.0, 44.1, 23.9, and 23.9, respectively). Conclusions When performing non-invasive ventilation among patients with de novo AHRF, it is important to avoid excessive tidal volume and lung injury. Although pressure support is needed for some of these patients, it should be applied with caution because this may lead to excessive tidal volume and lung injury. Trial registration (Protocol integer ID 49375, April 23, 2021). 10.17504/

2021 ◽  
Paul Paccaud ◽  
Diego Castanares-Zapatero ◽  
Ludovic Gerard ◽  
Virginie Montiel ◽  
Xavier Wittebole ◽  

Abstract Objective : Oxidative stress conditions may be responsible for an up-regulation of the expression of heme oxygenase (HO), the enzyme synthesizing carbon monoxide (CO) in cells. Elevated levels of arterial carboxyhemoglogin (aCOHb) have been found in critically ill patients, including those suffering from acute lung injury. We aimed to investigate the changes of aCOHb levels in COVID-19 critically ill patients.Design : Single center retrospective cohort study between March 1 and December 31, 2020.Setting: University teaching hospital with 900 beds including 48 ICU beds.Patients: Consecutive adults requiring ICU admission for severe COVID-19 infection.Measurements and main results : After exclusion of 23 patients who required extracorporeal membranous oxygenation (ECMO), a total of 135 patients was considered, from whom 76 required mechanical ventilation (MV) that was prolonged for more than 20 days in 28 patients. Demographics, laboratory values, treatment and outcomes were recorded. The evolution of aCOHb over time was investigated among survivors and non-survivors and among patients with or without MV. The admission and peak aCOHb values did not differ among survivors or non-survivors. In the patients with MV, there was a significant increase of aCOHb with time, with a biphasic evolution for the patients ventilated for more than 20 days: a parallel increase of aCOHb and PaCO2 followed by a trend to a plateau of aCOHb during PaCO2 recovery.Conclusions : Progressive increase in aCOHb from endogenous source is observed in COVID-19 patients requiring prolonged mechanical ventilation. Decrease of aCOHb appears slower than PaCO2 recovery.

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Weiwei Su ◽  
Qinglian Dong ◽  
Fangfang Jiao

Background. There is no better treatment method towards paraquat-induced acute lung injury (ALI) at present. Ambroxol combined with methylprednisolone exhibits a significant improvement effect on ALI treatment, whereas their mechanism in ALI is still unclear. Methods. 64 patients with ALI caused by paraquat poisoning brought to our hospital from January 2015 to January 2018 were selected. They were separated into a combined treatment group (CTG) and a routine treatment group (RTG) on the basis of different treatment methods. The survival of patients was observed after 7 days of treatment. Arterial blood gas, oxygen partial pressure (PaO2), partial pressure of carbon dioxide (PaCO2), oxygenation index (PaO2/FiO2), patient’s spontaneous respiratory rate (RR), tidal volume (VT), and positive end-expiratory pressure (PEEP) were observed before and after treatment for 7 days. Interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) were analyzed. The differences of indexes between the dead patients and the survivors were observed, and the potential predictive value of death was analyzed. Results. After treatment, the indexes of patients were significantly improved in both groups compared with those before therapy. Further comparison showed that the improvement of PaO2, PaCO2, and PaO2/FiO2 in CTG was obviously higher than that in RTG ( p < 0.05 ). The improvement of RR, PEEP, and VT in CTG was obviously higher than that in RTG ( p < 0.05 ). The decreased degree of IL-6 and TNF-α in CTG was higher than that in RTG ( p < 0.05 ). The 7-day mortality rate of 64 patients was 39.06%, and there was no obvious difference in the 7-day survival rate in both groups ( p = 0.649 ). IL-6 and TNF-α were expected to be potential prediction indexes of paraquat-induced ALI. Conclusion. Ambroxol combined with methylprednisolone significantly improved the oxygen partial pressure and oxygenation index of patients with paraquat-induced ALI and inhibited the inflammatory response of patients.

2021 ◽  
Vol 27 (44) ◽  
pp. 7669-7686
Chang-Ju Zhu ◽  
Wan-Guang Yang ◽  
De-Jian Li ◽  
Yao-Dong Song ◽  
San-Yang Chen ◽  

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