Prophylactic Noninvasive Ventilation Versus Conventional Care in Patients After Cardiac Surgery.

BACKGROUND: Cardiac surgery can be accompanied by postoperative complications, which are associated with increased postoperative morbidity and mortality. Therefore, it is necessary to investigate the effect of prophylactic noninvasive ventilation (NIV) after extubation versus conventional pulmonary care on complications after cardiac surgery. MATERIALS AND METHODS: An electronic search of PubMed, Cochrane Library, Ovid, and EMBASE was conducted to find randomized controlled trials which compared the effect of prophylactic NIV with controlled strategies on complications and which were published before April 2018. RESULTS: Ten studies (1011 patients) were included in the final analysis. The atelectasis rate was 32.6% in the prophylactic-NIV group, which was lower than that in the control group (48.71%). Prophylactic NIV could lower the rate of atelectasis, reintubation, and other respiratory complications (pleural effusion, pneumonia, and hypoxia) (odds ratio = 0.43, 0.33, and 0.45; 95% confidence interval: 0.21-0.88, 0. 13-0.84, 0.27-0.75; P = 0.02, 0.02, and 0.002, respectively). The effect on cardiac and distal organ complications (P = 0.07) and hospital mortality (P = 0.62) might be limited. CONCLUSIONS: Prophylactic NIV is associated with a lower rate of postoperative pulmonary complications. The effect on the other complications and hospital mortality might be limited. Further evidence with randomized controlled trials can discern the benefits.

Protocol for building an in vitro model of M2-like tumor-associated macrophages with lactic acid or conditioned medium from Lewis cells.

The model of M2-like tumor-associated macrophages (TAMs) is an increasingly attractive model for the study of TAMs. However, the detailed process of M2-like TAMs polarization induced by lactic acid or conditioned medium from Lewis cells (LCM) and the identification of M2-like TAMs is not yet available. In this protocol, we present the detailed methods to induce M2-like TAMs polarization and verify its functionality in order to better carry out related research. For complete details on the use and execution of this protocol, please refer to Fang et al.1.

Dynasore Alleviates LPS-Induced Acute Lung Injury by Inhibiting NLRP3 Inflammasome-Mediated Pyroptosis.

Background: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinically severe respiratory disorders without available pharmacological therapies. Dynasore is a cell-permeable molecule that inhibits GTPase activity and exerts protective effects in several disease models. However, whether dynasore can alleviate lipopolysaccharide (LPS)-induced ALI is unknown. This study investigated the effect of dynasore on macrophage activation and explored its potential mechanisms in LPS-induced ALI in vitro and in vivo. Methods: Bone marrow-derived macrophages (BMDMs) were activated classically with LPS or subjected to NLRP3 inflammasome activation with LPS+ATP. A mouse ALI model was established by the intratracheal instillation (i.t.) of LPS. The expression of PYD domains-containing protein 3 (NLRP3), caspase-1, and gasdermin D (GSDMD) protein was detected by Western blots. Inflammatory mediators were analyzed in the cell supernatant, in serum and bronchoalveolar lavage fluid (BALF) by enzyme-linked immunosorbent assays. Morphological changes in lung tissues were evaluated by hematoxylin and eosin staining. F4/80, Caspase-1 and GSDMD distribution in lung tissue was detected by immunofluorescence. Results: Dynasore downregulated nuclear factor (NF)-κB signaling and reduced proinflammatory cytokine production in vitro and inhibited the production and release of interleukin (IL)-1ß, NLRP3 inflammasome activation, and macrophage pyroptosis through the Drp1/ROS/NLRP3 axis. Dynasore significantly reduced lung injury scores and proinflammatory cytokine levels in both BALF and serum in vivo, including IL-1ß and IL-6. Dynasore also downregulated the co-expression of F4/80, caspase-1 and GSDMD in lung tissue. Conclusion: Collectively, these findings demonstrated that dynasore could alleviate LPS-induced ALI by regulating macrophage pyroptosis, which might provide a new therapeutic strategy for ALI/ARDS.

UK5099 Inhibits the NLRP3 Inflammasome Independently of its Long-Established Target Mitochondrial Pyruvate Carrier.

Targeting NLRP3 inflammasome has been recognized as a promising therapeutic strategy for the treatment of numerous common diseases. UK5099, a long-established inhibitor of mitochondrial pyruvate carrier (MPC), is previously found to inhibit macrophage inflammatory responses independent of MPC expression. However, the mechanisms by which UK5099 inhibit inflammatory responses remain unclear. Here, it is shown that UK5099 is a potent inhibitor of the NLRP3 inflammasome in both mouse and human primary macrophages. UK5099 selectively suppresses the activation of the NLRP3 but not the NLRC4 or AIM2 inflammasomes. Of note, UK5099 retains activities on NLRP3 in macrophages devoid of MPC expression, indicating this inhibitory effect is MPC-independent. Mechanistically, UK5099 abrogates mitochondria-NLRP3 interaction and in turn inhibits the assembly of the NLRP3 inflammasome. Further, a single dose of UK5099 persistently reduces IL-1ß production in an endotoxemia mouse model. Importantly, structure modification reveals that the inhibitory activities of UK5099 on NLRP3 are unrelated to the existence of the activated double bond within the UK5099 molecule. Thus, this study uncovers a previously unknown molecular target for UK5099, which not only offers a new candidate for the treatment of NLRP3-driven diseases but also confounds its use as an MPC inhibitor in immunometabolism studies.

Lactate induces tumor-associated macrophage polarization independent of mitochondrial pyruvate carrier-mediated metabolism.

Tumor cell-derived lactate has been recognized as the key driver of polarization in tumor-associated macrophages (TAMs). Intratumoral lactate can be transported into macrophages to fuel the TCA cycle, which is mediated by mitochondrial pyruvate carrier (MPC). At the heart of intracellular metabolism, MPC-mediated transport has been investigated in studies which suggested its role and importance in the process of TAMs polarization. However, previous studies relied on pharmacological inhibition instead of genetic approaches to evaluate the role of MPC in TAMs polarization. Here, we demonstrated that genetic depletion of MPC blocks the entry of lactate into mitochondria in macrophages. However, MPC-mediated metabolism was dispensable for IL-4/lactate-induced macrophages polarization as well as tumor growth. In addition, MPC depletion had no impact on hypoxia-inducible factor 1α (HIF-1α) stabilization and histone lactylation, both of which are required for TAMs polarization. Our study suggests that lactate itself, rather than its downstream metabolites, is responsible for TAMs polarization.

LINC00491 Facilitates Tumor Progression of Lung Adenocarcinoma via Wnt/ß-Catenin-Signaling Pathway by Regulating MTSS1 Ubiquitination.

Background: Long non-coding RNAs have been reported to be involved in tumorigenesis and progression through different regulatory mechanisms. It has been reported that aberrantly expressed long non-coding RNA LINC00491 promotes malignancy in multiple tumors, while the role of LINC00491 in lung adenocarcinoma (LUAD) is little reported and the mechanism for regulating tumor progression has not been elucidated. Methods: RNA sequencing and the TCGA database were combined to screen differentially expressed lncRNAs that facilitate tumor progression. The expression level of LINC00491 was examined in LUAD clinical samples and in cell lines using RT-qPCR. In vitro experiments including colony formation assay, EdU assay, cell migration and invasion assay and wound healing assay, and in vivo experiments including xenografting subcutaneous tumors and lung metastasis models were performed to investigate the function of LINC00491 in LUAD tumor progressions. RNA pull-down, mass spectrometry, RIP assays and truncation experiments were carried out to explore the proteins binding to LINC00491 and the specific interactions between the RNA-protein complex. Results: Our results showed that LINC0491 was significantly upregulated in LUAD and positively correlated with poor survival. High LINC00491 expression promoted proliferation, migration and invasion, and resulted in a high metastatic burden in LUAD. Using pull-down assay and mass spectrometry, MTSS1 was found binding to LINC00491, and the conducted experiments verified the direct interaction between LINC00491 and MTSS1. Meanwhile, LINC00491 was found to regulate MTSS1 degradation by promoting the MTSS1 ubiquitination level and then activating the Wnt/ß-catenin-signaling pathway. LINC00491/MTSS1/ß-catenin may act as a complex to facilitate tumor progression. Conclusions: In summary, our results found a novel mechanism in which LINC00491 directly interacts with MTSS1 by affecting its ubiquitination modification to promote LUAD proliferation, migration and invasion, then activating the Wnt/ß-catenin-signaling pathway, demonstrating its significant role in tumor progression and suggesting that the LINC00491/MTSS1/Wnt/ß-catenin-signaling pathway could serve as a potential therapeutic target for lung adenocarcinoma in the future.

TCF-1+ PD-1+ CD8+T cells are associated with the response to PD-1 blockade in non-small cell lung cancer patients.

PURPOSE: To determine whether TCF-1+PD-1+CD8+T cells are associated with the response to PD-1 blockade in non-small cell lung cancer (NSCLC) patients. METHODS: We investigated the expression of TCF-1+PD-1+CD8+T cells and elucidated their predictive role in NSCLC patients. Pretreatment specimens from 20 advanced NSCLC patients who underwent PD-1 immunotherapy or combined with chemotherapy were analyzed. The frequencies of TCF-1+ cells in PD-1+CD8+T cells were determined in these biospecimens using multi-label immunofluorescence staining and multi-spectral acquisition technology. The clinical roles of TCF-1+PD-1+CD8+T cells were assessed via analyzing our cases and human NSCLC data collected from public databases. RESULTS: A high frequency of TCF-1+PD-1+CD8+T cells was identified in responders compared with non-responders (p = 0.0024), and the patients with high expression of this cell subset had durable clinical benefit of anti-PD-1 therapy. There were no significant association between the expression of TCF-1+PD-1+CD8+T cells and patients' age, smoking history, pathologic type, and genetic status. In univariate analysis by the Cox hazard model, high frequency of TCF-1+ PD-1+ CD8+T cells was significantly correlated with patients' benefit of PD-1 blockade (p = 0.024). CONCLUSION: Our study indicated that TCF-1+PD-1+CD8+T cells are associated with the response to PD-1 blockade, and may be a predictor of anti-PD-1 therapy.

Progranulin Protects Against Airway Remodeling Through the Modulation of Autophagy via HMGB1 Suppression in House Dust Mite-Induced Chronic Asthma.

PURPOSE: Airway remodeling is an important feature of chronic asthma, and yet there are few effective therapeutic strategies. Progranulin (PGRN) has been shown to have lung protective functions, but the role of PGRN in asthmatic airway remodeling is unclear. We aim to explore the protective potential of PGRN on house dust mite (HDM)-induced airway remodeling and the underlying mechanisms. METHODS: In this study, a murine model of chronic asthma was established by HDM sensitization and challenge. Recombinant PGRN was intranasally administrated to mice during the phase of HDM challenge. TGF-ß1-treated human airway epithelial BEAS-2B cells were utilized to explore the effect of PGRN on airway epithelia exposed to profibrotic conditions and molecular mechanisms. RESULTS: We found that PGRN treatment attenuated HDM-induced airway remodeling, as evidenced by the suppression of collagen accumulation, mucus overproduction and airway smooth muscle synthesis in HDM-challenged asthmatic mice lungs. Meanwhile, PGRN also reversed the increased levels of autophagy markers and autophagosomes in airway epithelia under mimic asthmatic conditions, thereby controlling the fibrotic process in vivo and in vitro. Specifically, overexpressed HMGB1 and the subsequent RAGE/MAPKs signaling activation due to HDM exposure were abrogated in PGRN-treated asthmatic mice. Furthermore, knockdown of HMGB1 expression significantly restrained the fibrosis formation in TGF-ß1-induced airway epithelia accompanied by the downregulation of autophagic activity. However, enhancement of extracellular HMGB1 levels blunted the inhibition of autophagic flux by PGRN in airway epithelia, thereby resulting in the augmentation of collagen synthesis and fibrosis. CONCLUSION: Taken together, our data revealed that PGRN protected against asthmatic airway remodeling by negatively regulating autophagy via HMGB1 suppression, which might provide new insights into the therapeutic options for HDM-induced chronic asthma.

Progranulin Ameliorates Lung Inflammation in an LPS-induced Acute Lung Injury Mouse Model by Modulating Macrophage Polarization and the MAPK Pathway.

OBJECTIVE: Progranulin (PGRN) has been confirmed to exhibit anti-inflammatory activity. Nevertheless, the mechanisms of PGRN in acute lung injury (ALI) remain uncertain. The aim of this study was to explore the role of PGRN in a lipopolysaccharide (LPS)-induced ALI model and in primary bone marrow-derived macrophages, as well as to investigate the underlying mechanism of PGRN. METHODS: Mice were treated with recombinant PGRN protein to detect the effect of PGRN on mouse ALI. Bronchial alveolar lavage fluid (BALF) was analyzed to quantify the inflammatory cytokines, and the lung wet-to-dry ratio was calculated to assess the degree of pulmonary edema. Histological staining was completed on the lung tissues. CCK-8 assay was used to measure cell viability. Western blotting and quantitative polymerase chain reaction were performed to study the transcriptomic profiles during the MAPK pathway. RESULTS: Recombinant human PGRN significantly suppressed cellular inflammatory response, increased lung permeability, and reduced the expression of inflammatory proteins in the BALF and serum, which further improved survival time. Also, PGRN inhibited the LPS-induced M1 marker gene expression and enhanced the M2 marker gene expression in vivo and in vitro. Further analysis revealed that PGRN suppresses the activity of the MAPK pathway in LPS-treated macrophages in a dose-dependent manner. CONCLUSION: PGRN exhibited anti-inflammatory activity and regulated macrophage polarization by suppressing the phosphorylation of the MAPK pathway.

Noninvasive ventilation with a helmet in patients with acute respiratory failure caused by chest trauma: a randomized controlled trial.

Noninvasive ventilation (NIV) is beneficial in acute respiratory failure (ARF) caused by chest trauma; however, NIV-related complications affect the efficacy. We evaluated whether NIV with helmet decreases the incidence of complications and improves its effects in a single center. Patients with ARF after chest trauma were randomized to receive NIV with helmet or face mask. The primary outcome was the rate of NIV-related complications. Secondary outcomes were PaO2/FiO2, patient's tolerance, intubation rate, length of intensive care unit (ICU) stay, and ICU mortality. The trial was terminated early after an interim analysis with 59 patients. The incidence of complications was lower in the helmet group [10% (3/29) vs 43% (13/30), P = 0.004], and PaO2/FiO2s were higher at 1 h and at the end of NIV (253.14 ± 64.74 mmHg vs 216.06 ± 43.86 mmHg, 277.07 ± 84.89 mmHg vs 225.81 ± 63.64 mmHg, P = 0.013 and 0.012) compared with them in face mask group. More patients reported excellent tolerance of the helmet vs face mask after 4 h of NIV [83% (24/29) vs 47% (14/30), P = 0.004] and at the end of NIV [69% (20/29) vs 30% (9/30), P = 0.03]. Differences in intubation rate, ICU stay, and mortality were non-significant (P = 0.612, 0.100, 1.000, respectively). NIV with helmet decreased NIV-related complications, increased PaO2/FiO2, and improved tolerance compared with NIV with face mask in patients with chest trauma.Trial registration: Registered in the Chinese Clinical Trial Registry (ChiCTR1900025915), a WHO International Clinical Trials Registry Platform ( http://www.chictr.org.cn/searchprojen.aspx ).

Early Percutaneous Dilational Tracheostomy in Trauma Patients After Anterior Cervical Fusion: Propensity-Matched Cohort Study.

BACKGROUND: Patients with cervical spinal cord injuries (CSCIs) may be required to undergo tracheostomy. However, in patients undergoing anterior cervical fusion (ACF), percutaneous dilational tracheostomy (PDT) may be delayed given the risk of cross-contamination. We aimed to evaluate the risk of surgical site infection (SSI) in early PDT in patients with traumatic CSCI after ACF. METHODS: All trauma patients admitted to the intensive care unit from 2008 to 2018 were retrospectively analyzed. Patients with CSCIs who underwent both ACF and PDT were identified, with or without posterior cervical fusion. Cases were classified as having undergone early PDT (≤4 days after ACF) versus late PDT (>4 days after ACF). Propensity scores were matched, and outcomes were compared between matched groups to reduce confounding by indication. RESULTS: From a total of 133 enrolled patients, a well-balanced propensity-matched cohort of 68 patients was defined. On the basis of the comparison of outcomes after matching, no significant difference in SSI was observed between both groups. There was no patient with SSI in the early PDT group (0%), whereas there were 2 SSI patients (5.9%) in the late PDT group (P = 0.493): The tracheostomy site was involved in 1, and the posterior approach site was involved in the other. Early PDT was associated with a shorter duration of mechanical ventilation (P = 0.042). There were no significant differences in the length of intensive care unit stay and hospital mortality between groups. CONCLUSIONS: Early PDT within 4 days after ACF did not increase the risk of SSI compared with late PDT in patients with traumatic CSCIs.

Noninvasive Ventilation as a Weaning Strategy in Subjects with Acute Hypoxemic Respiratory Failure.

BACKGROUND: Weaning through noninvasive ventilation (NIV) after early extubation may facilitate invasive ventilation withdrawal and reduce related complications in patients with hypercapnic respiratory failure. However, the effects of NIV weaning are uncertain in patients with acute hypoxemic respiratory failure (AHRF). We aimed to investigate whether NIV weaning could reduce hospital mortality and other outcomes compared with invasive weaning in subjects with hypoxemic AHRF. METHODS: We searched medical literature databases for relevant articles published from inception to February 2019. Randomized controlled trials that adopted NIV as a weaning strategy compared with invasive weaning in hypoxemic AHRF were included. The primary outcome was hospital mortality. The secondary outcomes included ICU mortality, the ICU stay, weaning time, duration of ventilation, extubation failure, and adverse events. RESULTS: Six relevant studies, which involved 718 subjects, were included. There was no significant effect of NIV weaning on hospital mortality compared with invasive weaning (risk ratio 0.94, 95% CI 0.65-1.36; P = .74), whereas there was a significant effect of NIV weaning on shortening the ICU stay (mean difference -3.95, 95% CI -6.49 to -1.40, P = .002) and on decreasing adverse events without affecting the weaning time (standardized MD -0.04, 95% CI -0.21 to 0.14; P = .68). CONCLUSIONS: The strategy of NIV weaning did not decrease hospital mortality in subjects with hypoxemic AHRF, but it did shorten the ICU lengths of stay and reduce adverse events.

[Non-invasive ventilation with helmet in patients with respiratory failure caused by acute exacerbation of chronic obstructive pulmonary disease].

OBJECTIVE: To investigate the effect and tolerance of non-invasive ventilation (NIV) with helmet in patients with respiratory failure caused by acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and the effect on improving blood gas, alleviating dyspnea and the occurrence of complications. METHODS: Patients with AECOPD and respiratory failure admitted to emergency intensive care unit (EICU) and respiratory intensive care unit (RICU) of the First Affiliated Hospital of Zhengzhou University from January 1st, 2018 to May 31st, 2019 were enrolled. After obtaining the informed consent of the patients or their authorized family members, the patients were divided into two groups: the helmet group and the facial mask group by random number table. NIV was carried out by using helmet or facial mask, respectively. During the course of NIV (immediately, 1 hour, 4 hours and at the end of NIV), the tolerance score, blood gas analysis, heart rate (HR), respiratory rate (RR) of patients were monitored, and the incidence of tracheal intubation, in-hospital mortality and complications were observed. Kaplan-Meier survival curve was plotted to analyze the 30-day cumulative survival of the two groups. RESULTS: A total of 82 patients with AECOPD and respiratory failure were included during the study period. After excluding patients with the oxygenation index (PaO2/FiO2) > 200 mmHg (1 mmHg = 0.133 kPa), with tracheal intubation or invasive ventilation, suffering from acute myocardial infarction, severe trauma within 2 weeks, excessive secretion, sputum discharge disorder or refusal to participate in the study, 26 patients were finally enrolled in the analysis, randomly assigned to the helmet group and the facial mask group, with 13 patients in each group. The PaO2/FiO2 after NIV of patients in both groups was increased significantly as compared with that immediately after NIV, without significant difference between the two groups, but the increase in PaO2/FiO2 at the end of NIV compared with immediately after NIV in the helmet group was significantly higher than that in the facial mask group (mmHg: 75.1±73.2 vs. 7.7±86.0, P < 0.05). RR at each time point after NIV in the two groups was lower than that immediately after NIV, especially in the helmet group. There were significant differences between the helmet group and facial mask group at 1 hour, 4 hours, and the end of NIV (times/min: 17.5±4.1 vs. 23.1±6.3 at 1 hour, 16.2±2.5 vs. 20.0±5.5 at 4 hours, 15.5±2.5 vs. 21.2±5.9 at the end of NIV, all P < 0.05). The NIV tolerance score of the helmet group at 4 hours and the end was significantly higher than that of the facial mask group (4 hours: 3.9±0.3 vs. 3.3±0.9, at the end of NIV: 3.8±0.6 vs. 2.9±0.9, both P < 0.05). There was no significant difference in the improvement of pH value, arterial partial pressure of carbon dioxide (PaCO2), or HR between helmet group and facial mask group. The total number of complications (cases: 3 vs. 8) and the nasal skin lesions (cases: 0 vs. 4) in the helmet group were significantly less than those in the facial mask group (both P < 0.05). Only 2 patients in the helmet group received endotracheal intubation, and 1 of them died; 5 patients in the facial mask group received endotracheal intubation, and 3 of them died; there was no significant difference between the two groups (both P > 0.05). The Kaplan-Meier survival curve analysis showed that the cumulative survival rate of 30 days in the helmet group was lower than that in the facial mask group, but the difference was not statistically significant (Log-Rank test: χ2 = 1.278, P = 0.258). CONCLUSIONS: NIV with helmet has better comfort for patients with AECOPD combined with respiratory failure, and better effect on improving oxygenation and relieving dyspnea, and its effect on carbon dioxide emissions is not inferior to that of traditional mask NIV.

[Effect of lung strain on breathing mechanics in dogs with acute respiratory distress syndrome].

OBJECTIVE: To explore the effect of lung strain on breathing mechanics in dogs with acute respiratory distress syndrome (ARDS). METHODS: Twenty-four healthy male Beagle dogs were recruited to reproduce medium ARDS models with venous injection of 0.18 mL/kg oleic acid, and they were randomly assigned to five groups with random numbers table method. In lung protective ventilation (LPV) group (n = 4), the ventilation was supported for 24 hours with tidal volume (VT) at 6-8 mL/kg, and in lung strain 1.0, 1.5, 2.0, 2.5 groups (S1.0, S1.5, S2.0, S2.5 groups), the VT was calculated from lung strain, the volume recruitment by positive end expiratory pressure (VPEEP) and functional residual capacity (FRC). Five groups were given mechanical ventilation for 24 hours or until reaching the end point of the experiment [when the dosage of norepinephrine was higher than 1.4 µg×kg-1×min-1, the blood pressure was still lower than 60 mmHg (1 mmHg = 0.133 kPa) for more than 30 minutes, which was regarded as the end point of the experiment]. Static lung compliance (Cst), airway plateau pressure (Pplat) and lung stress during the experiment were recorded. Linear regression analysis was used to fit the regression equations of lung strain and Cst descending rate, Pplat and lung stress for analyzing their relationships. RESULTS: The VT of group LPV was (7.1±0.5) mL/kg. With the increase of lung strain, VT was gradually increased. VT of group S1.0 [(7.3±1.8) mL/kg] was similar to group LPV. VT of groups S1.5, S2.0, S2.5 was significantly higher than that of group LPV (mL/kg: 13.3±5.5, 18.7±5.4, 20.1±7.4 vs. 7.1±0.5, all P < 0.05). Moreover, under the same lung strain, the difference in VT among individuals was large. The Cst of each group was decreased significantly at the end of the experiment as compared with that before model reproduction. With the increase of lung strain, the rate of Cst descending was increased, Cst dropped more significantly in groups S2.0 and S2.5 than that in groups S1.0 and S1.5 [(48.0±15.0)%, (54.4±9.5)% vs. (25.9±13.7)%, (38.6±8.1)%, all P < 0.05]. Pplat and pulmonary stress at model reproduction in all groups were significantly higher than those before model reproduction, and they increased with the prolongation of ventilation time. Pplat and lung stress at 4 hours of ventilation in group S1.5 were significantly higher than those in group LPV [Pplat (cmH2O, 1 cmH2O = 0.098 kPa): 26.2±2.3 vs. 20.2±4.2, lung stress (cmH2O): 20.5±2.0 vs. 16.6±2.5, both P < 0.05], and they increased with lung strain increasing till to the end of experiment. It was shown by correlation analysis that lung strain was positively related with Cst descending rate, Pplat and lung stress at 4 hours of ventilation (r value was 0.716, 0.660, 0.539, respectively, all P < 0.05), which indicated a strong linear correlation. It was shown by fitting linear regression analysis that when lung strain increased by 1, Cst descending rate increased by 19.0% [95% confidence interval (95%CI) = 14.6-23.3, P = 0.000], Pplat increased by 10.8 cmH2O (95%CI = 7.9-13.7, P = 0.002), and the lung stress increased by 7.4 cmH2O (95%CI = 4.7-10.2, P = 0.002). CONCLUSIONS: In animal ARDS models, the larger the lung strain, the higher the Pplat and lung stress during mechanical ventilation, VT originated for lung strain 2.0 and 2.5 may further reduce Cst in ARDS models, when lung strain over 1.5, Pplat and lung stress increased significantly, which exceeded the safe range of LPV (35 cmH2O and 25 cmH2O, respectively), and further aggravated ventilator induced lung injury (VILI).