Injuria pulmonar autoinducida por el paciente / Patient self-inflicted lung injury

La Injuria Pulmonar Autoinducida por el Paciente (p-SILI) es una entidad recientemente reconocida. Clásicamente, el daño producido por la ventilación mecánica (VM) se asoció al uso de presión positiva, y para disminuirlo se crearon distintas estrategias conocidas como parámetros de protección pulmonar. Sin embargo, es importante reconocer los potenciales efectos deletéreos de la ventilación espontánea dependientes de la injuria pulmonar previa que sufra el paciente y del esfuerzo que realice. En este artículo se explican los distintos mecanismos que pueden producir p-SILI y las estrategias descritas en la literatura para prevenirla (AU)

Patient self-inflicted lung injury (p-SILI) is a recently recognized disorder. Classically, damage produced by mechanical ventilation (MV) was associated with the use of positive pressure, and different strategies known as lung protection parameters were created to reduce it. Nevertheless, it is important to recognize the potential deleterious effects of the effort made during spontaneous breathing due to previous lung injury suffered by the patient. This article explains the different mechanisms that may produce p-SILI and the prevention strategies described in the literature. (AU)

The association between regional transcriptome profiles and lung volumes in response to mechanical ventilation and lung injury.

BACKGROUND: Lung inhomogeneity plays a pivotal role in the development of ventilator-induced lung injury (VILI), particularly in the context of pre-existing lung injury. The mechanisms that underlie this interaction are poorly understood. We aimed to elucidate the regional transcriptomic response to mechanical ventilation (MV), with or without pre-existing lung injury, and link this to the regional lung volume response to MV. METHODS: Adult female BALB/c mice were randomly assigned into one of four groups: Saline, MV, lipopolysaccharide (LPS) or LPS/MV. Lung volumes (tidal volume, Vt; end-expiratory volume, EEV) were measured at baseline or after 2 h of ventilation using four-dimensional computed tomography (4DCT). Regional lung tissue samples corresponding to specific imaging regions were analysed for the transcriptome response by RNA-Seq. Bioinformatics analyses were conducted and the regional expression of dysregulated gene clusters was then correlated with the lung volume response. RESULTS: MV in the absence of pre-existing lung injury was associated with regional variations in tidal stretch. The addition of LPS also caused regional increases in EEV. We identified 345, 141 and 184 region-specific differentially expressed genes in response to MV, LPS and LPS/MV, respectively. Amongst these candidate genes, up-regulation of genes related to immune responses were positively correlated with increased regional tidal stretch in the MV group, while dysregulation of genes associated with endothelial barrier related pathways were associated with increased regional EEV and Vt when MV was combined with LPS. Further protein-protein interaction analysis led to the identification of two protein clusters representing the PI3K/Akt and MEK/ERK signalling hubs which may explain the interaction between MV and LPS exposure. CONCLUSION: The biological pathways associated with lung volume inhomogeneity during MV, and MV in the presence of pre-existing inflammation, differed. MV related tidal stretch induced up-regulation of immune response genes, while LPS combined with MV disrupted PI3K/Akt and MEK/ERK signalling.

Diallyl Disulfide Attenuates STAT3 and NF-κB Pathway Through PPAR-γ Activation in Cerulein-Induced Acute Pancreatitis and Associated Lung Injury in Mice.

We have previously shown that diallyl disulfide (DADS) protects mice against cerulein-induced acute pancreatitis (AP) and associated lung injury. However, the molecular mechanisms underlying its effect and the components involved have not been studied. We hypothesized that DADS may reduce TNF-α, CSE expression, H2S production, STAT3, and NF-κB activation and induce SOCS3 expression through peroxisome proliferator-activated receptor γ (PPAR-γ) pathway in cerulein-induced mice. Male Swiss mice were treated with hourly intraperitoneal injections of cerulein (50 µg/kg) for 6 h. Diallyl disulfide (200 µg/kg) was administered in the presence or absence of PPAR-γ antagonist GW9662 (0.3 mg/kg) (i.p) 1 h after the induction of AP. Our findings revealed that DADS blocked TNF-α, CSE expression, H2S production, and STAT3, and NF-κB activation was reversed by GW9662. Furthermore, GW9662 abrogated DADS-induced SOCS3 expression. The results show for the first that DADS-induced anti-inflammatory effect in acute pancreatitis is regulated through PPAR-γ.

Potential roles of mesenchymal stem cells and their exosomes in the treatment of COVID-19.

Background: Corona Virus Disease 2019 (COVID-19) is an acute respiratory infectious disease caused by severe respiratory syndrome coronavirus 2 (SARS-CoV-2). The primary pathogenesis is over-activation of the immune system. SARS-CoV-2 continues to mutate and spread rapidly and no effective treatment options are yet available. Mesenchymal stem cells (MSCs) are known to induce anti-inflammatory macrophages, regulatory T cells and dendritic cells. There are a rapidly increasing number of clinical investigations of cell-based therapy approaches for COVID-19. Objective: To summarize the pathogenic mechanism of SARS-CoV-2, and systematically formulated the immunomodulation of COVID-19 by MSCs and their exosomes, as well as research progress. Method: Searching PubMed, clinicaltrials.gov and Chictr.cn for eligible studies to be published or registered by May 2021. Main keywords and search strategies were as follows: ((Mesenchymal stem cells) OR (MSCs)) AND (COVID-19). Results: MSCs regulate the immune system to prevent cytokine release syndrome (CRS) and to promote endogenous repair by releasing various paracrine factors and exosomes. Conclusions: MSC therapy is thus a promising candidate for COVID-19.

The effects of inhaling hydrogen gas on macrophage polarization, fibrosis, and lung function in mice with bleomycin-induced lung injury.

BACKGROUND: Acute respiratory distress syndrome, which is caused by acute lung injury, is a destructive respiratory disorder caused by a systemic inflammatory response. Persistent inflammation results in irreversible alveolar fibrosis. Because hydrogen gas possesses anti-inflammatory properties, we hypothesized that daily repeated inhalation of hydrogen gas could suppress persistent lung inflammation by inducing functional changes in macrophages, and consequently inhibit lung fibrosis during late-phase lung injury. METHODS: To test this hypothesis, lung injury was induced in mice by intratracheal administration of bleomycin (1.0 mg/kg). Mice were exposed to control gas (air) or hydrogen (3.2% in air) for 6 h every day for 7 or 21 days. Respiratory physiology, tissue pathology, markers of inflammation, and macrophage phenotypes were examined. RESULTS: Mice with bleomycin-induced lung injury that received daily hydrogen therapy for 21 days (BH group) exhibited higher static compliance (0.056 mL/cmH2O, 95% CI 0.047-0.064) than mice with bleomycin-induced lung injury exposed only to air (BA group; 0.042 mL/cmH2O, 95% CI 0.031-0.053, p = 0.02) and lower static elastance (BH 18.8 cmH2O/mL, [95% CI 15.4-22.2] vs. BA 26.7 cmH2O/mL [95% CI 19.6-33.8], p = 0.02). When the mRNA levels of pro-inflammatory cytokines were examined 7 days after bleomycin administration, interleukin (IL)-6, IL-4 and IL-13 were significantly lower in the BH group than in the BA group. There were significantly fewer M2-biased macrophages in the alveolar interstitium of the BH group than in the BA group (3.1% [95% CI 1.6-4.5%] vs. 1.1% [95% CI 0.3-1.8%], p = 0.008). CONCLUSIONS: The results suggest that hydrogen inhalation inhibits the deterioration of respiratory physiological function and alveolar fibrosis in this model of lung injury.

Irradiation Activates MZF1 to Inhibit miR-541-5p Expression and Promote Epithelial-Mesenchymal Transition (EMT) in Radiation-Induced Pulmonary Fibrosis (RIPF) by Upregulating Slug.

Understanding miRNAs regulatory roles in epithelial-mesenchymal transition (EMT) would help establish new avenues for further uncovering the mechanisms underlying radiation-induced pulmonary fibrosis (RIPF) and identifying preventative and therapeutic targets. Here, we demonstrated that miR-541-5p repression by Myeloid Zinc Finger 1 (MZF1) promotes radiation-induced EMT and RIPF. Irradiation could decrease miR-541-5p expression in vitro and in vivo and inversely correlated to RIPF development. Ectopic miR-541-5p expression suppressed radiation-induced-EMT in vitro and in vivo. Knockdown of Slug, the functional target of miR-541-5p, inhibited EMT induction by irradiation. The upregulation of transcription factor MZF1 upon irradiation inhibited the expression of endogenous miR-541-5p and its primary precursor (pri-miR-541-5p), which regulated the effect of the Slug on the EMT process. Our finding showed that ectopic miR-541-5p expression mitigated RIPF in mice by targeting Slug. Thus, irradiation activates MZF1 to downregulate miR-541-5p in alveolar epithelial cells, promoting EMT and contributing to RIPF by targeting Slug. Our observation provides further understanding of the development of RIPF and determines potential preventative and therapeutic targets.

Spirometry quality predictors in a large multistate prospective study.

BACKGROUND: The Gulf Long-Term Follow-up (GuLF) Study is a prospective cohort study of health effects associated with oil spill response and clean-up following the 2010 Deepwater Horizon Disaster (DWH). As part of the study, spirometry testing of lung function was carried out in home visits across multiple states. Few studies have described factors associated with spirometry test failure in field-based settings. OBJECTIVE: Our objective was to identify what factors, if any, predict test failure among GuLF Study participants who completed spirometry testing in a non-traditional setting. METHODS: Trained examiners administered spirometry (May 2011-May 2013) to 10,019 participants living in US Gulf States (LA, MS, TX, AL, FL) using an Easy-on ultrasonic spirometer. We applied American Thoracic Society/European Respiratory Society quality criteria to determine quality test failure and identified factors predictive of failure using both a Stepwise and a LASSO model. We calculated odds ratios and 95% confidence intervals (CIs) for associations of selected factors with test failure. RESULTS: Among GuLF Study participants who conducted spirometry, self-reported African American/Black participants (OR: 1.39, 95% CI: 1.23,1.56); men (OR:1.61, 95% CI: 1.41,1.83); and those making less than $20,000 per year (OR: 1.45, 95% CI: 1.26,1.67) were more likely to fail quality testing, while those who were obese were less likely to fail (OR: 0.61, 95% CI: 0.42,0.89). CONCLUSION: Field-based studies involving spirometry should identify and account for participant factors that may influence test failure. Coaching that is tailored to those less likely to have experience with spirometry may help reduce test failure rates.

Effect of positive end-expiratory pressure on lung injury and haemodynamics during experimental acute respiratory distress syndrome treated with extracorporeal membrane oxygenation and near-apnoeic ventilation.

BACKGROUND: Lung rest has been recommended during extracorporeal membrane oxygenation (ECMO) for severe acute respiratory distress syndrome (ARDS). Whether positive end-expiratory pressure (PEEP) confers lung protection during ECMO for severe ARDS is unclear. We compared the effects of three different PEEP levels whilst applying near-apnoeic ventilation in a model of severe ARDS treated with ECMO. METHODS: Acute respiratory distress syndrome was induced in anaesthetised adult male pigs by repeated saline lavage and injurious ventilation for 1.5 h. After ECMO was commenced, the pigs received standardised near-apnoeic ventilation for 24 h to maintain similar driving pressures and were randomly assigned to PEEP of 0, 10, or 20 cm H2O (n=7 per group). Respiratory and haemodynamic data were collected throughout the study. Histological injury was assessed by a pathologist masked to PEEP allocation. Lung oedema was estimated by wet-to-dry-weight ratio. RESULTS: All pigs developed severe ARDS. Oxygenation on ECMO improved with PEEP of 10 or 20 cm H2O, but did not in pigs allocated to PEEP of 0 cm H2O. Haemodynamic collapse refractory to norepinephrine (n=4) and early death (n=3) occurred after PEEP 20 cm H2O. The severity of lung injury was lowest after PEEP of 10 cm H2O in both dependent and non-dependent lung regions, compared with PEEP of 0 or 20 cm H2O. A higher wet-to-dry-weight ratio, indicating worse lung injury, was observed with PEEP of 0 cm H2O. Histological assessment suggested that lung injury was minimised with PEEP of 10 cm H2O. CONCLUSIONS: During near-apnoeic ventilation and ECMO in experimental severe ARDS, 10 cm H2O PEEP minimised lung injury and improved gas exchange without compromising haemodynamic stability.

Dynamic Metabolic Risk Profiling of World Trade Center Lung Disease: A Longitudinal Cohort Study.

Rationale: Metabolic syndrome (MetSyn) increases the risk of World Trade Center (WTC) lung injury (LI). However, the temporal relationship of MetSyn, exposure intensity, and lung dysfunction is not well understood. Objective: To model the association of longitudinal MetSyn characteristics with WTC lung disease to define modifiable risk. Methods: Firefighters, for whom consent was obtained (N = 5,738), were active duty on September 11, 2001 (9/11). WTC-LI (n = 1,475; FEV1% predicted

The central nervous system during lung injury and mechanical ventilation: a narrative review.

Mechanical ventilation induces a number of systemic responses for which the brain plays an essential role. During the last decade, substantial evidence has emerged showing that the brain modifies pulmonary responses to physical and biological stimuli by various mechanisms, including the modulation of neuroinflammatory reflexes and the onset of abnormal breathing patterns. Afferent signals and circulating factors from injured peripheral tissues, including the lung, can induce neuronal reprogramming, potentially contributing to neurocognitive dysfunction and psychological alterations seen in critically ill patients. These impairments are ubiquitous in the presence of positive pressure ventilation. This narrative review summarises current evidence of lung-brain crosstalk in patients receiving mechanical ventilation and describes the clinical implications of this crosstalk. Further, it proposes directions for future research ranging from identifying mechanisms of multiorgan failure to mitigating long-term sequelae after critical illness.

Evaluation on epithelial-mesenchymal state and microRNAs focusing on isolated alveolar epithelial cells from bleomycin injured rat lung.

Several studies using bleomycin (BLM)-induced lung injury rat model revealed that epithelial-mesenchymal transition (EMT) contributes to pulmonary fibrosis. Conversely, microRNAs (miRNAs) are considered as useful markers of various diseases. In the present study, we aimed to characterize the EMT state through focusing on alveolar epithelial cells and identify the miRNAs that can be used as markers to predict pulmonary fibrosis using a BLM-induced lung injury rat model. Intratracheal administration of BLM increased hydroxyproline, a component of collagen, in lung tissues at day 14, but not at day 7. However, BLM induced EMT at day 7, which was accompanied with increased mRNA expression of α-smooth muscle actin, a representative EMT marker, in alveolar epithelium, thereby suggesting that EMT occurs prior to pulmonary fibrosis in alveolar epithelial cells. Using this rat model, the expression levels of several EMT-associated miRNAs were examined, and miR-222 was found to be upregulated in alveolar epithelial cells as well as bronchoalveolar lavage fluid from day 3. Our findings indicate that EMT in alveolar epithelial cells may occur before pulmonary fibrosis, and miR-222 may be used as a potential marker for early prediction of pulmonary fibrosis.

Monitoring lung injury with particle flow rate in LPS- and COVID-19-induced ARDS.

In severe acute respiratory distress syndrome (ARDS), extracorporeal membrane oxygenation (ECMO) is a life-prolonging treatment, especially among COVID-19 patients. Evaluation of lung injury progression is challenging with current techniques. Diagnostic imaging or invasive diagnostics are risky given the difficulties of intra-hospital transportation, contraindication of biopsies, and the potential for the spread of infections, such as in COVID-19 patients. We have recently shown that particle flow rate (PFR) from exhaled breath could be a noninvasive, early detection method for ARDS during mechanical ventilation. We hypothesized that PFR could also measure the progress of lung injury during ECMO treatment. Lipopolysaccharide (LPS) was thus used to induce ARDS in pigs under mechanical ventilation. Eight were connected to ECMO, whereas seven animals were not. In addition, six animals received sham treatment with saline. Four human patients with ECMO and ARDS were also monitored. In the pigs, as lung injury ensued, the PFR dramatically increased and a particular spike followed the establishment of ECMO in the LPS-treated animals. PFR remained elevated in all animals with no signs of lung recovery. In the human patients, in the two that recovered, PFR decreased. In the two whose lung function deteriorated while on ECMO, there was increased PFR with no sign of recovery in lung function. The present results indicate that real-time monitoring of PFR may be a new, complementary approach in the clinic for measurement of the extent of lung injury and recovery over time in ECMO patients with ARDS.

Addition of 5% CO2 to Inspiratory Gas Prevents Lung Injury in an Experimental Model of Pulmonary Artery Ligation.

Rationale: Unilateral ligation of the pulmonary artery may induce lung injury through multiple mechanisms, which might be dampened by inhaled CO2. Objectives: This study aims to characterize bilateral lung injury owing to unilateral ligation of the pulmonary artery in healthy swine undergoing controlled mechanical ventilation and its prevention by 5% CO2 inhalation and to investigate relevant pathophysiological mechanisms. Methods: Sixteen healthy pigs were allocated to surgical ligation of the left pulmonary artery (ligation group), seven to surgical ligation of the left pulmonary artery and inhalation of 5% CO2 (ligation + FiCO2 5%), and six to no intervention (no ligation). Then, all animals received mechanical ventilation with Vt 10 ml/kg, positive end-expiratory pressure 5 cm H2O, respiratory rate 25 breaths/min, and FiO2 50% (±FiCO2 5%) for 48 hours or until development of severe lung injury. Measurements and Main Results: Histological, physiological, and quantitative computed tomography scan data were compared between groups to characterize lung injury. Electrical impedance tomography and immunohistochemistry analysis were performed in a subset of animals to explore mechanisms of injury. Animals from the ligation group developed bilateral lung injury as assessed by significantly higher histological score, larger increase in lung weight, poorer oxygenation, and worse respiratory mechanics compared with the ligation + FiCO2 5% group. In the ligation group, the right lung received a larger fraction of Vt and inflammation was more represented, whereas CO2 dampened both processes. Conclusions: Mechanical ventilation induces bilateral lung injury within 48 hours in healthy pigs undergoing left pulmonary artery ligation. Inhalation of 5% CO2 prevents injury, likely through decreased stress to the right lung and antiinflammatory effects.

Interactive toxicity effect of combined exposure to hematite and amorphous silicon dioxide nanoparticles in human A549 cell line.

The study on the health effects of combined exposure to various contaminants has been recommended by many authors. The objective of the present study was to examine the effects of the co-exposure to hematite and amorphous silicon dioxide (A-SiO2) nanoparticles on the human lung A549 cell line. The A549 cell line was exposed to 10, 50, 100, and 250 µg/ml concentrations of hematite and A-SiO2 nanoparticles both independently and in combination. Their toxicity in both circumstances was investigated by MTT, intracellular reactive oxygen species, cell glutathione content, and mitochondrial membrane potential tests, and the type of interaction was investigated by statistical analysis using Statistical Package for Social Sciences (SPSS, v. 21). Results showed that the independent exposure to either hematite or A-SiO2 compared with the control group produced more toxic effects on the A549 cell line. The toxicity of combined exposure of the nanoparticles was lower compared with independent exposure, and antagonistic interactive effects were detected. The findings of this study could be useful in clarifying the present debate on the health effects of combined exposure of hematite and A-SiO2 nanoparticles. Because of the complexities of combined exposures, further studies of this kind are recommended.

The Improvement Effect of Sodium Ferulate on the Formation of Pulmonary Fibrosis in Silicosis Mice Through the Neutrophil Alkaline Phosphatase 3 (NALP3)/Transforming Growth Factor-ß1 (TGF-ß1)/α-Smooth Muscle Actin (α-SMA) Pathway.

BACKGROUND Pneumoconiosis is a chronic progressive fibrotic interstitial pneumonia for which the pathogenesis and treatment remain unclear. Previous studies showed that sodium ferulate (SF) may have a therapeutic effect, and this study explored the mechanism underlying SF-related improvement. MATERIAL AND METHODS In this study, a silicosis mouse model and primary cultured mouse lung fibroblasts were established. Hematoxylin-eosin staining, western blot analysis, quantitative real-time polymerase chain reaction, and Masson staining were used to observe the lung injury, expression of vimentin, and the degree of pulmonary fibrosis. The extracted lung fibroblasts were identified by immunofluorescence. The expression of fibrosis-related genes encoding transforming growth factor-ß1 (TGF-ß1), neutrophil alkaline phosphatase 3 (NALP3), collagen-1, alpha-smooth muscle actin (alpha-SMA), and phosphorylated p38 (p-p38) and p38 proteins were detected by western blot. The effects of SF and the TGF-ß pathway agonist SRI-011381 on cell proliferation and the expression of fibrosis-related protein in mouse lung fibroblasts were measured by Cell Counting Kit-8, immunofluorescence, and western blot as needed. RESULTS SF reduced the lung lesions in silicosis mice and inhibited the expression of vimentin and fibrosis-related genes, while having no effect on body weight. Vimentin expression was positive in the extracted cells. In vitro experiments showed that SF inhibited the proliferation of lung fibroblasts and the expression of fibrosis-related proteins. In addition, SF partly reversed the opposite regulatory effect of SRI-011381 on lung fibroblasts. CONCLUSIONS SF inhibited lung injury and fibrosis in silicosis mice through the NALP3/TGF-ß1/alpha-SMA pathway.

Pulmonary Apical Cap as a Potential Risk Factor for Pleuroparenchymal Fibroelastosis.

Pleuroparenchymal fibroelastosis (PPFE) is a progressive and frequently fatal interstitial lung disease that involves the upper lobes. Although its cause remains unknown, the histopathologic evidence underlying PPFE bears striking resemblance to that of the pulmonary apical cap (PAC), a relatively common and benign entity. We describe the case of a patient with PAC that evolved into distinctly asymmetric PPFE over 6 years after unilateral surgical lung injury. Given the histologic similarity between these two conditions, we propose that these two entities underlie common biologic pathways of abnormal response to lung injury, with the presence of a PAC increasing susceptibility to the development of PPFE in the face of ongoing inflammatory insults. This case describes the histopathologic evolution of PAC to PPFE before and after an inciting injury.

Simulated aeromedical evacuation exacerbates burn induced lung injury: targeting mitochondrial DNA for reversal.

BACKGROUND: Aeromedical evacuation of patients with burn trauma is an important transport method in times of peace and war, during which patients are exposed to prolonged periods of hypobaric hypoxia; however, the effects of such exposure on burn injuries, particularly on burn-induced lung injuries, are largely unexplored. This study aimed to determine the effects of hypobaric hypoxia on burn-induced lung injuries and to investigate the underlying mechanism using a rat burn model. METHODS: A total of 40 male Wistar rats were randomly divided into four groups (10 in each group): sham burn (SB) group, burn in normoxia condition (BN) group, burn in hypoxia condition (BH) group, and burn in hypoxia condition with treatment intervention (BHD) group. Rats with 30% total body surface area burns were exposed to hypobaric hypoxia (2000 m altitude simulation) or normoxia conditions for 4 h. Deoxyribonuclease I (DNase I) was administered systemically as a treatment intervention. Systemic inflammatory mediator and mitochondrial deoxyribonucleic acid (mtDNA) levels were determined. A histopathological evaluation was performed and the acute lung injury (ALI) score was determined. Malonaldehyde (MDA) content, myeloperoxidase (MPO) activity, and the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome level were determined in lung tissues. Data among groups were compared using analysis of variance followed by Tukey's test post hoc analysis. RESULTS: Burns resulted in a remarkably higher level of systemic inflammatory cytokines and mtDNA release, which was further heightened by hypobaric hypoxia exposure (P < 0.01). Moreover, hypobaric hypoxia exposure gave rise to increased NLRP3 inflammasome expression, MDA content, and MPO activity in the lung (P < 0.05 or P < 0.01). Burn-induced lung injuries were exacerbated, as shown by the histopathological evaluation and ALI score (P < 0.01). Administration of DNase I markedly reduced mtDNA release and systemic inflammatory cytokine production. Furthermore, the NLRP3 inflammasome level in lung tissues was decreased and burn-induced lung injury was ameliorated (P < 0.01). CONCLUSIONS: Our results suggested that simulated aeromedical evacuation further increased burn-induced mtDNA release and exacerbated burn-induced inflammation and lung injury. DNase I reduced the release of mtDNA, limited mtDNA-induced systemic inflammation, and ameliorated burn-induced ALI. The intervening mtDNA level is thus a potential target to protect from burn-induced lung injury during aeromedical conditions and provides safer air evacuations for severely burned patients.

Proteomic Analysis Revealed the Characteristics of Key Proteins Involved in the Regulation of Inflammatory Response, Leukocyte Transendothelial Migration, Phagocytosis, and Immune Process during Early Lung Blast Injury.

Previous studies found that blast injury caused a significant increased expression of interleukin-1, IL-6, and tumor necrosis factor, a significant decrease in the expression of IL-10, an increase in Evans blue leakage, and a significant increase in inflammatory cell infiltration in the lungs. However, the molecular characteristics of lung injury at different time points after blast exposure have not yet been reported. Therefore, in this study, tandem mass spectrometry (TMT) quantitative proteomics and bioinformatics analysis were used for the first time to gain a deeper understanding of the molecular mechanism of lung blast injury at different time points. Forty-eight male C57BL/6 mice were randomly divided into six groups: control, 12 h, 24 h, 48 h, 72 h, and 1 w after low-intensity blast exposure. TMT quantitative proteomics and bioinformatics analysis were performed to analyze protein expression profiling in the lungs from control and blast-exposed mice, and differential protein expression was verified by Western blotting. The results demonstrated that blast exposure induced severe lung injury, leukocyte infiltration, and the production of inflammatory factors in mice. After analyzing the expression changes in global proteins and inflammation-related proteomes after blast exposure, the results showed that a total of 6861 global proteins and 608 differentially expressed proteins were identified, of which 215, 128, 187, 232, and 65 proteins were identified at 12 h, 24 h, 48 h, 72 h, and 1 week after blast exposure, respectively. Moreover, blast exposure-induced 177 differentially expressed proteins were associated with inflammatory responses, which were enriched in the inflammatory response regulation, leukocyte transendothelial migration, phagocytosis, and immune response. Therefore, blast exposure may induce early inflammatory response of lung tissue by regulating the expression of key proteins in the inflammatory process, suggesting that early inflammatory response may be the initiating factor of lung blast injury. These data can provide potential therapeutic candidates or approaches for the development of future treatment of lung blast injury.

Diminishing Efficacy of Prone Positioning With Late Application in Evolving Lung Injury.

OBJECTIVES: It is not known how lung injury progression during mechanical ventilation modifies pulmonary responses to prone positioning. We compared the effects of prone positioning on regional lung aeration in late versus early stages of lung injury. DESIGN: Prospective, longitudinal imaging study. SETTING: Research imaging facility at The University of Pennsylvania (Philadelphia, PA) and Medical and Surgical ICUs at Massachusetts General Hospital (Boston, MA). SUBJECTS: Anesthetized swine and patients with acute respiratory distress syndrome (acute respiratory distress syndrome). INTERVENTIONS: Lung injury was induced by bronchial hydrochloric acid (3.5 mL/kg) in 10 ventilated Yorkshire pigs and worsened by supine nonprotective ventilation for 24 hours. Whole-lung CT was performed 2 hours after hydrochloric acid (Day 1) in both prone and supine positions and repeated at 24 hours (Day 2). Prone and supine images were registered (superimposed) in pairs to measure the effects of positioning on the aeration of each tissue unit. Two patients with early acute respiratory distress syndrome were compared with two patients with late acute respiratory distress syndrome, using electrical impedance tomography to measure the effects of body position on regional lung mechanics. MEASUREMENTS AND MAIN RESULTS: Gas exchange and respiratory mechanics worsened over 24 hours, indicating lung injury progression. On Day 1, prone positioning reinflated 18.9% ± 5.2% of lung mass in the posterior lung regions. On Day 2, position-associated dorsal reinflation was reduced to 7.3% ± 1.5% (p < 0.05 vs Day 1). Prone positioning decreased aeration in the anterior lungs on both days. Although prone positioning improved posterior lung compliance in the early acute respiratory distress syndrome patients, it had no effect in late acute respiratory distress syndrome subjects. CONCLUSIONS: The effects of prone positioning on lung aeration may depend on the stage of lung injury and duration of prior ventilation; this may limit the clinical efficacy of this treatment if applied late.