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Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are clinical syndromes characterized by acute lung inflammation, pulmonary edema and hypoxemia, with up to 50% mortality rate without effective pharmacological therapy. Following the acute inflammation, repair and remodeling occurs which in some cases resulting in lung fibrosis. The pathophysiology of ALI/ARDS remains incompletely understood. Lipopolysaccharide (LPS)-induced ALI in mice have been widely used as a model to study human ALI/ARDS. Isthmin 1 (ISM1) is a secreted protein highly abundant in mouse lung. We have previously reported that upon intratracheal LPS instillation, ISM1 expression in the lung is further upregulated. Recently, we also reported that ISM1 is an anti-inflammatory protein in the lung with Ism1-/- mice presenting spontaneous chronic low-grade lung inflammation and obvious emphysema at young adult stage. However, what role ISM1 plays in ALI/ARDS and lung fibrosis remain unclear.
Sepsis is the leading cause of lung injury in adults and can lead to acute respiratory distress syndrome (ARDS). Using a novel technique of isolated in vivo lung perfusion (IVLP), we hypothesized that normothermic IVLP will improve oxygenation and compliance in a porcine model of sepsis-induced lung injury.
Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury (ALI) resulting in life-threatening hypoxaemia. Although ARDS can be caused by a variety of pathogens or major trauma, it is best known as the major cause of mortality in COVID-19 patients. Since ARDS is often associated with dysregulated inflammatory immune responses, immunomodulatory approaches represent a possible treatment option. The objective of this study was to evaluate the therapeutic potential of interleukin (IL)-1 blockade using Anakinra in a mouse model of lipopolysaccharide (LPS)-induced ALI.
In pulmonary inflammation, recruitment of circulating polymorphonuclear leukocytes is essential for host defense and initiates the following specific immune response. One pathological hallmark of acute lung injury and acute respiratory distress syndrome is the uncontrolled transmigration of neutrophils into the lung interstitium and alveolar space. Thereby, the extravasation of leukocytes from the vascular system into the tissue is induced by chemokines that are released from the site of inflammation. The most relevant chemokine receptors of neutrophils are CXC chemokine receptor (CXCR) 1 and CXCR2. CXCR2 is of particular interest since several studies implicate a pivotal role of this receptor in development and promotion of numerous inflammatory disorders. CXCR2 gets activated by ELR(+) chemokines, including MIP-2, KC (rodents) and IL-8 (human). Since multiple ELR(+) CXC chemokines act on both receptors--CXCR1 and CXCR2--a pharmacologic agent blocking both receptors seems to be advantageous. So far, several CXCR1/2 antagonists have been developed and have been tested successfully in experimental studies. A newly designed CXCR1 and CXCR2 antagonist can be orally administered and was for the first time found efficient in humans. This review highlights the role of CXCR2 in acute lung injury and discusses its potential as a therapeutic target.
Background and Objective: Lung-protective mechanical ventilation is known to attenuate ventilator-associated lung injury (VALI), but often at the expense of hypoventilation and hypercapnia. It remains unclear whether the main mechanism by which VALI is attenuated is a product of limiting mechanical forces to the lung during ventilation, or a direct biological effect of hypercapnia. Methods: Acute lung injury (ALI) was induced in 60 anesthetized rats by the instillation of 1.25 M HCl into the lungs via tracheostomy. Ten rats each were randomly assigned to one of six experimental groups and ventilated for 4 h with: 1) Conventional HighV E Normocapnia (high VT, high minute ventilation, normocapnia), 2) Conventional Normocapnia (high VT, normocapnia), 3) Protective Normocapnia (VT 8 ml/kg, high RR), 4) Conventional iCO 2 Hypercapnia (high VT, low RR, inhaled CO2), 5) Protective iCO 2 Hypercapnia (VT 8 ml/kg, high RR, added CO2), 6) Protective endogenous Hypercapnia (VT 8 ml/kg, low RR). Blood gasses, broncho-alveolar lavage fluid (BALF), and tissue specimens were collected and analyzed for histologic and biologic lung injury assessment. Results: Mild ALI was achieved in all groups characterized by a decreased mean PaO2/FiO2 ratio from 428 to 242 mmHg (p < 0.05), and an increased mean elastance from 2.46 to 4.32 cmH2O/L (p < 0.0001). There were no differences in gas exchange among groups. Wet-to-dry ratios and formation of hyaline membranes were significantly lower in low VT groups compared to conventional tidal volumes. Hypercapnia reduced diffuse alveolar damage and IL-6 levels in the BALF, which was also true when CO2 was added to conventional VT. In low VT groups, hypercapnia did not induce any further protective effect except increasing pulmonary IL-10 in the BALF. No differences in lung injury were observed when hypercapnia was induced by adding CO2 or decreasing minute ventilation, although permissive hypercapnia decreased the pH significantly and decreased liver histologic injury. Conclusion: Our findings suggest that low tidal volume ventilation likely attenuates VALI by limiting mechanical damage to the lung, while hypercapnia attenuates VALI by limiting pro-inflammatory and biochemical mechanisms of injury. When combined, both lung-protective ventilation and hypercapnia have the potential to exert an synergistic effect for the prevention of VALI.
Proline-rich tyrosine kinase 2 (Pyk2) is essential in neutrophil degranulation and chemotaxis in vitro. However, its effect on the process of lung inflammation and edema formation during LPS induced acute lung injury (ALI) remains unknown. The goal of the present study was to determine the effect of inhibiting Pyk2 on LPS-induced acute lung inflammation and injury in vivo.
Arterial oxygen saturation has not been assessed sequentially in conscious mice as a direct consequence of an in vivo murine model of acute lung injury. Here, we report daily changes in arterial oxygen saturation and other cardiopulmonary parameters by using infrared pulse oximetry following intratracheal lipopolysaccharide (IT-LPS) for up to 9 days, and following IT-phosphate buffered saline up to 72 h as a control. We show that arterial oxygen saturation decreases, with maximal decline at 96 h post IT-LPS. Blood oxygen levels negatively correlate with 7 of 10 quantitative markers of murine lung injury, including neutrophilia and interleukin-6 expression. This identifies infrared pulse oximetry as a method to non-invasively monitor arterial oxygen saturation following direct LPS instillations.
Acute lung injury (ALI) occurs frequently in patients with severe traumatic brain injury (TBI) and is associated with a poor clinical outcome. Aquaporins (AQPs), particularly AQP1 and AQP4, maintain water balances between the epithelial and microvascular domains of the lung. Since pulmonary edema (PE) usually occurs in the TBI-induced ALI patients, we investigated the effects of a thaliporphine derivative, TM-1, on the expression of AQPs and histological outcomes in the lung following TBI in rats. TM-1 administered (10 mg/kg, intraperitoneal injection) at 3 or 4 h after TBI significantly reduced the elevated mRNA expression and protein levels of AQP1 and AQP4 and diminished the wet/dry weight ratio, which reflects PE, in the lung at 8 and 24 h after TBI. Postinjury TM-1 administration also improved histopathological changes at 8 and 24 h after TBI. PE was accompanied with tissue pathological changes because a positive correlation between the lung injury score and the wet/dry weight ratio in the same animal was observed. Postinjury administration of TM-1 improved ALI and reduced PE at 8 and 24 h following TBI. The pulmonary-protective effect of TM-1 may be attributed to, at least in part, downregulation of AQP1 and AQP4 expression after TBI.
Acute lung injury is one of major complications associated with sepsis, responsible for morbidity and mortality. Patients who suffer from acute lung injury often require respiratory support under sedations, and it would be important to know the role of sedatives in lung injury. We examined volatile anesthetic isoflurane, which is commonly used in surgical setting, but also used as an alternative sedative in intensive care settings in European countries and Canada. We found that isoflurane exposure attenuated neutrophil recruitment to the lungs in mice suffering from experimental polymicrobial abdominal sepsis. We found that isoflurane attenuated one of major neutrophil chemoattractants LTB4 mediated response via its receptor BLT1 in neutrophils. Furthermore, we have shown that isoflurane directly bound to BLT1 by a competition assay using newly developed labeled BLT1 antagonist, suggesting that isoflurane would be a BLT1 antagonist.
Acute lung injury (ALI) is a syndrome that is characterised by acute inflammation and tissue injury that affects normal gas exchange in the lungs. Hallmarks of ALI include dysfunction of the alveolar-capillary membrane resulting in increased vascular permeability, an influx of inflammatory cells into the lung and a local pro-coagulant state. Patients with ALI present with severe hypoxaemia and radiological evidence of bilateral pulmonary oedema. The syndrome has a mortality rate of approximately 35% and usually requires invasive mechanical ventilation. ALI can follow direct pulmonary insults, such as pneumonia, or occur indirectly as a result of blood-borne insults, commonly severe bacterial sepsis. Although animal models of ALI have been developed, none of them fully recapitulate the human disease. The differences between the human syndrome and the phenotype observed in animal models might, in part, explain why interventions that are successful in models have failed to translate into novel therapies. Improved animal models and the development of human in vivo and ex vivo models are therefore required. In this article, we consider the clinical features of ALI, discuss the limitations of current animal models and highlight how emerging human models of ALI might help to answer outstanding questions about this syndrome.
Chemo-radiotherapy and systemic therapies have proven satisfactory outcomes as standard treatments for various thoracic malignancies; however, adverse pulmonary effects, like pneumonitis, can be life-threatening. Pneumonitis is caused by direct cytotoxic effect, oxidative stress, and immune-mediated injury. Radiotherapy Induced Lung Injury (RILI) encompasses two phases: an early phase known as Radiation Pneumonitis (RP), characterized by acute lung tissue inflammation as a result of exposure to radiation; and a late phase called Radiation Fibrosis (RF), a clinical syndrome that results from chronic pulmonary tissue damage. Currently, diagnoses are made by exclusion using clinical assessment and radiological findings. Pulmonary function tests have constituted a significant step in evaluating lung function status during radiotherapy and useful predictive tools to avoid complications or limit toxicity. Systemic corticosteroids are widely used to treat pneumonitis complications, but its use must be standardized, and consider in the prophylaxis setting given the fatal outcome of this adverse event. This review aims to discuss the clinicopathological features of pneumonitis and provide practical clinical recommendations for prevention, diagnosis, and management.
We tested the hypothesis that at the early phase of acute lung injury (ALI) the degree of endothelium injury may predict lung parenchyma remodelling. For this purpose, two models of extrapulmonary ALI induced by Escherichia coli lipopolysaccharide (ALI-LPS) or cecal ligation and puncture (ALI-CLP) were developed in mice. At day 1, these models had similar degrees of lung mechanical compromise, epithelial damage, and intraperitoneal inflammation, but endothelial lesion was greater in ALI-CLP. A time course analysis revealed, at day 7: ALI-CLP had higher degrees of epithelial lesion, denudation of basement membrane, endothelial damage, elastic and collagen fibre content, neutrophils in bronchoalveolar lavage fluid (BALF), peritoneal fluid and blood, levels of interleukin-6, KC (murine analogue of IL-8), and transforming growth factor-β in BALF. Conversely, the number of lung apoptotic cells was similar in both groups. In conclusion, the intensity of fibroelastogenesis was affected by endothelium injury in addition to the maintenance of epithelial damage and intraperitoneal inflammation.
Acute lung injury (ALI) is one of the most common clinical emergencies with limited effective pharmaceutical treatment in the clinic, especially when it progresses to acute respiratory distress syndrome (ARDS). Currently, mesenchymal stem cells (MSCs) exhibit specific superiority for ALI/ARDS treatment. However, stem cells from different sources may result in controversial effects on similar disease conditions. This study aimed to determine the effects of human amnion-derived mesenchymal stem cells (hAMSCs) on two different ALI mice model. The administered hAMSCs effectively accumulated in the lung tissues in all hAMSC-treated groups. Compared with the model and 1% human serum albumin (HSA) groups, high-dose hAMSCs (1.0 × 106 cells) group significantly alleviated alveolar-capillary permeability, oxidative stress, inflammatory factors level and histopathological damage. In addition, the NF-κB signaling pathway is one of the key pathways activated during lipopolysaccharide (LPS) or paraquat (PQ)-induced lung injury. Our results indicated that hAMSCs (1.0 × 106 cells) obviously inhibited the expression of p-IKKα/β, p-IκBα, and p-p65 in the lung tissue (p < 0.05). The high-dose (HD) hAMSC treatment exerted beneficial therapeutic effects on ALI mice models without detectable adverse reactions. The therapeutic effect of hAMSCs might involve NF-κB signaling pathway inhibition. hAMSC treatment is a potential candidate therapy for ALI.
Different medical therapies are employed in acute lung injury (ALI) but there is still a debate about the efficacy of these drugs. Among these therapies steroids are clinically applied and bosentan is experimentally studied. The aim of this study was to evaluate the efficacy of these two drugs to treat inflammation in ALI by histopathological comparison.
Renal ischemia reperfusion injury (IRI) after surgery may promote acute lung injury (ALI) by inducing an inflammatory response. However, the underlying molecular mechanism is still unclear. Studies have reported that inhibitor of κB kinase (IKK)ε primarily regulates inflammation and cell proliferation. The present study aimed to investigate the regulatory role of IKKε in ALI in mice, in order to provide an experimental basis for preventing ALI following surgery‑induced renal IRI. C57BL/6J wild‑type (WT) and IKKε knockout (IKKε‑/‑) mice underwent bilateral renal pedicle occlusion. The plasma creatinine concentration, urea nitrogen level and lung wet‑to‑dry ratio were measured at baseline, and at 24 and 48 h after declamping. The histological localization and protein levels of inflammatory factors, such as tumor necrosis factor (TNF)‑α, interleukin (IL)‑1β and IL‑10, were analyzed in lung tissues. Subsequently, the interactions between IKKε and components of the nuclear factor (NF)‑κB pathway were studied. The results of the present study demonstrated that the IKKε‑/‑ groups displayed similar renal function but less pulmonary edema compared with that of the WT groups. The levels of proinflammatory factors in the lungs were significantly upregulated in WT mice compared with those in IKKε‑/‑ mice after IRI surgery. The NF‑κB pathway components and downstream factors were substantially upregulated in the WT groups after acute ischemic kidney injury, and these effects were significantly inhibited in the IKKε‑/‑ groups. Based on these data, the present study hypothesized that IKKε may serve a negative role in kidney‑lung crosstalk after renal IRI and may be a novel target for the treatment of patients with renal IRI.
Background: Numerous potential ARDS therapeutics, based upon preclinical successful rodent studies that utilized LPS challenge without mechanical ventilation, have failed in Phase 2/3 clinical trials. Recently, ALT-100 mAb, a novel biologic that neutralizes the TLR4 ligand and DAMP, eNAMPT (extracellular nicotinamide phosphoribosyltransferase), was shown to reduce septic shock/VILI-induced porcine lung injury when delivered 2 h after injury onset. We now examine the ALT-100 mAb efficacy on acute kidney injury (AKI) and lung fluid balance in a porcine ARDS/VILI model when delivered 6 h post injury. Methods/Results: Compared to control PBS-treated pigs, exposure of ALT-100 mAb-treated pigs (0.4 mg/kg, 2 h or 6 h after injury initiation) to LPS-induced pneumonia/septic shock and VILI (12 h), demonstrated significantly diminished lung injury severity (histology, BAL PMNs, plasma cytokines), biochemical/genomic evidence of NF-kB/MAP kinase/cytokine receptor signaling, and AKI (histology, plasma lipocalin). ALT-100 mAb treatment effectively preserved lung fluid balance reflected by reduced BAL protein/tissue albumin levels, lung wet/dry tissue ratios, ultrasound-derived B lines, and chest radiograph opacities. Delayed ALT-100 mAb at 2 h was significantly more protective than 6 h delivery only for plasma eNAMPT while trending toward greater protection for remaining inflammatory indices. Delayed ALT-100 treatment also decreased lung/renal injury indices in LPS/VILI-exposed rats when delivered up to 12 h after LPS. Conclusions: These studies indicate the delayed delivery of the eNAMPT-neutralizing ALT-100 mAb reduces inflammatory lung injury, preserves lung fluid balance, and reduces multi-organ dysfunction, and may potentially address the unmet need for novel therapeutics that reduce ARDS/VILI mortality.
Severe injury occurs in the lung after acute spinal cord injury (ASCI) and autophagy is inhibited. However, rapamycin-activated autophagy's role and mechanism in lung injury development after ASCI is unknown. Preventing lung injury after ASCI by regulating autophagy is currently a valuable and unknown area. Herein, we aimed to investigate the effect and possible mechanism of rapamycin-activated autophagy on lung damage post-ASCI. An experimental animal study of rapamycin's effect and mechanism on lung damage after ASCI. We randomly divided 144 female wild-type Sprague-Dawley rats into a vehicle sham group (n = 36), a vehicle injury group (n = 36), a rapamycin sham group (n = 36), and a rapamycin injury group (n = 36). The spine was injured at the tenth thoracic vertebra using Allen's method. At 12, 24, 48, and 72 h after surgery, the rats were killed humanely. Lung damage was evaluated via pulmonary gross anatomy, lung pathology, and apoptosis assessment. Autophagy induction was assessed according to LC3, RAB7, and Beclin 1 levels. ULK-1, ULK-1 Ser555, ULK-1 Ser757, AMPK α and AMPK β1/2 were used to investigate the potential mechanism. After rapamycin pretreatment, the lung showed no obvious damage (e.g., cell death, inflammatory exudation, hemorrhage, and pulmonary congestion) at 12 h and 48 h after injury and Beclin1, LC3 and RAB7 levels increased. After rapamycin pretreatment, ULK-1, ULK-1 Ser555, and ULK-1 Ser757 levels increased at 12 h and 48 h after injury compared with the vehicle group, but they decreased at 12 h after injury compared with the rapamycin sham group. After rapamycin pretreatment, AMPKα levels did not change significantly before and after injury; however, at 48 h after injury, its level was elevated significantly compared with that in the vehicle group. Rapamycin can prevent lung injury after ASCI, possibly via upregulation of autophagy through the AMPK-mTORC1-ULK1 regulatory axis.
Single-lung ventilation (SLV) associated acute lung injury is similar to ischemia reperfusion (IR) injury which is usually occurred during lung surgery. Olmesartan (Olm), a novel angiotensin receptor blocker (ARB), has been reported to ameliorate organ IR injury. Several recent studies have shown that lung microbiota may be involved in pulmonary diseases, but the effect of pulmonary microbiota in SLV-induced lung injury has not been reported. This study aims to determine the mechanism of how Olm attenuates SLV induced lung injury. Our data showed that 7 days Olm treatment before modeling markedly alleviated SLV-induced lung injury by suppressing inflammation and reactive oxygen species. Bronchoalveolar lavage fluid samples from the injured side were collected for 16S rRNA gene-based sequencing analysis and 53 different bacteria at the genus and species levels were identified. Furthermore, the injured lung samples were collected for metabolomics analysis using liquid chromatography-mass spectrometry analyses to explore differential metabolites. The Kyoto Encyclopedia of Genes and Genomes (KEGG) was applied to analyze the correlation between differential metabolites and lung microbiota. A total of 38 pathways were identified according to differential metabolites and 275 relevant pathways were enriched via analyzing the microbial community, 24 pathways were both identified by analyzing either metabolites or microbiota, including pyrimidine metabolism, purine metabolism, aminoacyl-tRNA biosynthesis and ATP-binding cassette transporter. Besides classical blockage of the renin-angiotensin II system, Olm could also alleviate SLV-induced lung injury by rewiring the interaction between pulmonary microbiota and metabolites.
Acute kidney injury (AKI) complicated by acute lung injury has a detrimental effect on mortality among critically ill patients. Recently, a renal ischemia-reperfusion (IR) model suggested the involvement of histones and neutrophil extracellular traps (NETs) in the development of distant lung injury after renal IR. Given that recombinant thrombomodulin (rTM) has anti-inflammatory roles by binding to circulating histones, we aimed to clarify its effect on distant lung injury induced by AKI in a murine bilateral renal IR model. Both pretreatment and delayed treatment with rTM significantly decreased pulmonary myeloperoxidase activity, but they did not affect renal dysfunction at 24 h after renal IR. Additionally, rTM mitigated the renal IR-augmented expression of proinflammatory cytokines (tumor necrosis factor-α, interleukin-6, and keratinocyte-derived chemokine), and vascular leakage, as well as the degree of lung damage. Intense histone accumulation and active NET formation occurred in both the kidneys and the lungs; however, rTM significantly decreased the histone and NET accumulation only in the lungs. Administration of rTM may have protective impact on the lungs after renal IR by blocking histone and NET accumulation in the lungs, although no protection was observed in the kidneys. Treatment with rTM may be an adjuvant strategy to attenuate distant lung injury complicating AKI.
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