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.

Antibodies can initiate lung injury in a variety of disease states such as autoimmunity, transfusion reactions, or after organ transplantation, but the key factors determining in vivo pathogenicity of injury-inducing antibodies are unclear. A previously overlooked step in complement activation by IgG antibodies has been elucidated involving interactions between IgG Fc domains that enable assembly of IgG hexamers, which can optimally activate the complement cascade. Here, we tested the in vivo relevance of IgG hexamers in a complement-dependent alloantibody model of acute lung injury. We used three approaches to block alloantibody hexamerization (antibody carbamylation, the K439E Fc mutation, or treatment with domain B from Staphylococcal protein A), all of which reduced acute lung injury. Conversely, Fc mutations promoting spontaneous hexamerization made a harmful alloantibody into a more potent inducer of acute lung injury and rendered an innocuous alloantibody pathogenic. Treatment with a recombinant Fc hexamer 'decoy' therapeutic protected mice from lung injury, including in a model with transgenic human FCGR2A expression that exacerbated pathology. These results indicate a direct in vivo role of IgG hexamerization in initiating acute lung injury and the potential for therapeutics that inhibit or mimic hexamerization to treat antibody-mediated diseases.

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.

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.

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.

Acute kidney injury (AKI) is a common and serious complication following lung transplantation (LTx), and it is associated with high mortality and morbidity. This study assessed the incidence of AKI after LTx and analyzed the associated perioperative factors and clinical outcomes.

Patients with acute kidney injury (AKI) have increased mortality; data suggest that the duration, not just severity, of AKI predicts increased mortality. Animal models suggest that AKI is a multisystem disease that deleteriously affects the lungs, heart, brain, intestine, and liver; notably, these effects have only been examined within 48 h, and longer term effects are unknown. In this study, we examined the longer term systemic effects of AKI, with a focus on lung injury. Mice were studied 7 days after an episode of ischemic AKI (22 min of renal pedicle clamping and then reperfusion) and numerous derangements were present including (1) lung inflammation; (2) increased serum proinflammatory cytokines; (3) liver injury; and (4) increased muscle catabolism. Since fluid overload may cause respiratory complications post-AKI and fluid management is a critical component of post-AKI care, we investigated various fluid administration strategies in the development of lung inflammation post-AKI. Four different fluid strategies were tested - 100, 500, 1000, or 2000 μL of saline administered subcutaneously daily for 7 days. Interestingly, at 7 days post-AKI, the 1000 and 2000 μL fluid groups had less severe AKI and less severe lung inflammation versus the 100 and 500 μL groups. In summary, our data demonstrate that appropriate fluid management after an episode of ischemic AKI led to both (1) faster recovery of kidney function and (2) significantly reduced lung inflammation, consistent with the notion that interventions to shorten AKI duration have the potential to reduce complications and improve patient outcomes.

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/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.

Loss of control in the trafficking of immune cells to the inflamed lung tissue contributes to the pathogenesis of life-threatening acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS). Targeting CXCR7 has been proposed as a potential therapeutic approach to reduce pulmonary inflammation; however, its role and its crosstalk with the two chemokine receptors CXCR3 and CXCR4 via their shared ligands CXCL11 and CXCL12 is not yet completely understood. The present paper aimed to characterize the pathological role of the CXCR3/CXCR4/CXCR7 axis in a murine model of ALI. Lipopolysaccharide (LPS) inhalation in mice resulted in the development of key pathologic features of ALI/ARDS, including breathing dysfunctions, alteration in the alveolar capillary barrier, and lung inflammation. LPS inhalation induced immune cell infiltration into the bronchoalveolar space, including CXCR3+ and CXCR4+ cells, and enhanced the expression of the ligands of these two chemokine receptors. The first-in-class CXCR7 antagonist, ACT-1004-1239, increased levels of CXCL11 and CXCL12 in the plasma without affecting their levels in inflamed lung tissue, and consequently reduced CXCR3+ and CXCR4+ immune cell infiltrates into the bronchoalveolar space. In the early phase of lung inflammation, characterized by a massive influx of neutrophils, treatment with ACT-1004-1239 significantly reduced the LPS-induced breathing pattern alteration. Both preventive and therapeutic treatment with ACT-1004-1239 reduced lung vascular permeability and decreased inflammatory cell infiltrates. In conclusion, these results demonstrate a key pathological role of CXCR7 in ALI/ARDS and highlight the clinical potential of ACT-1004-1239 in ALI/ARDS pathogenesis.

Acute Lung Injury (ALI) is a life-threatening, diffuse heterogeneous lung injury characterized by acute onset, pulmonary edema and respiratory failure. Lipopolysaccharide (LPS) is a common cause of both direct and indirect lung injury and when administered to a mouse induces a lung phenotype exhibiting some of the clinical characteristics of human ALI. Here, we report that LPS inhalation in mice results in increased bronchoalveolar lavage fluid (BALF) levels of Autotaxin (ATX, Enpp2), a lysophospholipase D largely responsible for the conversion of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA) in biological fluids and chronically inflamed sites. In agreement, gradual increases were also detected in BALF LPA levels, following inflammation and pulmonary edema. However, genetic or pharmacologic targeting of ATX had minor effects in ALI severity, suggesting no major involvement of the ATX/LPA axis in acute inflammation. Moreover, systemic, chronic exposure to increased ATX/LPA levels was shown to predispose to and/or to promote acute inflammation and ALI unlike chronic inflammatory pathophysiological situations, further suggesting a differential involvement of the ATX/LPA axis in acute versus chronic pulmonary inflammation.

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 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.

Nitrogen mustard (NM) is an alkylating vesicant that causes severe pulmonary injury. Currently, there are no effective means to counteract vesicant-induced lung injury. MG53 is a vital component of cell membrane repair and lung protection. Here, we show that mice with ablation of MG53 are more susceptible to NM-induced lung injury than the wild-type mice. Treatment of wild-type mice with exogenous recombinant human MG53 (rhMG53) protein ameliorates NM-induced lung injury by restoring arterial blood oxygen level, by improving dynamic lung compliance and by reducing airway resistance. Exposure of lung epithelial and endothelial cells to NM leads to intracellular oxidative stress that compromises the intrinsic cell membrane repair function of MG53. Exogenous rhMG53 protein applied to the culture medium protects lung epithelial and endothelial cells from NM-induced membrane injury and oxidative stress, and enhances survival of the cells. Additionally, we show that loss of MG53 leads to increased vulnerability of macrophages to vesicant-induced cell death. Overall, these findings support the therapeutic potential of rhMG53 to counteract vesicant-induced lung injury.

The receptor for advanced glycation end-products (RAGE) is involved in inflammatory response during acute respiratory distress syndrome (ARDS). Growing body of evidence support strategies of RAGE inhibition in experimental lung injury, but its modalities and effects remain underinvestigated. Anesthetised C57BL/6JRj mice were divided in four groups; three of them underwent orotracheal instillation of acid and were treated with anti-RAGE monoclonal antibody (mAb) or recombinant soluble RAGE (sRAGE), acting as a decoy receptor. The fourth group served as a control. Lung injury was assessed by the analysis of blood gases, alveolar permeability, histology, AFC, and cytokines. Lung expression and distribution epithelial channels ENaC, Na,K-ATPase, and aquaporin (AQP)-5 were assessed. Treatment with either anti-RAGE mAb or sRAGE improved lung injury, arterial oxygenation and decreased alveolar inflammation in acid-injured animals. Anti-RAGE therapies were associated with restored AFC and increased lung expression of AQP-5 in alveolar cell. Blocking RAGE had potential therapeutic effects in a translational mouse model of ARDS, possibly through a decrease in alveolar type 1 epithelial cell injury as shown by restored AFC and lung AQP-5 expression. Further mechanistic studies are warranted to describe intracellular pathways that may control such effects of RAGE on lung epithelial injury and repair.

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.

Systems biology offers considerable promise in uncovering novel pathways by which viruses and other microbial pathogens interact with host signaling and expression networks to mediate disease severity. In this study, we have developed an unbiased modeling approach to identify new pathways and network connections mediating acute lung injury, using severe acute respiratory syndrome coronavirus (SARS-CoV) as a model pathogen. We utilized a time course of matched virologic, pathological, and transcriptomic data within a novel methodological framework that can detect pathway enrichment among key highly connected network genes. This unbiased approach produced a high-priority list of 4 genes in one pathway out of over 3,500 genes that were differentially expressed following SARS-CoV infection. With these data, we predicted that the urokinase and other wound repair pathways would regulate lethal versus sublethal disease following SARS-CoV infection in mice. We validated the importance of the urokinase pathway for SARS-CoV disease severity using genetically defined knockout mice, proteomic correlates of pathway activation, and pathological disease severity. The results of these studies demonstrate that a fine balance exists between host coagulation and fibrinolysin pathways regulating pathological disease outcomes, including diffuse alveolar damage and acute lung injury, following infection with highly pathogenic respiratory viruses, such as SARS-CoV.

Phosgene (Carbonyl Chloride, COCl2) remains an important chemical intermediate in many industrial processes such as combustion of chlorinated hydrocarbons and synthesis of solvents (degreasers, cleaners). It is a sweet smelling gas, and therefore does not prompt escape by the victim upon exposure. Supplemental oxygen and ventilation are the only available management strategies. This study was aimed to delineate the pathogenesis and identify novel biomarkers of acute lung injury post exposure to COCl2 gas. Adult male and female C57BL/6 mice (20-25 g), exposed to COCl2 gas (10 or 20 ppm) for 10 min in environmental chambers, had a dose dependent reduction in PaO2 and an increase in PaCO2, 1 day post exposure. However, mortality increased only in mice exposed to 20 ppm of COCl2 for 10 min. Correspondingly, these mice (20 ppm) also had severe acute lung injury as indicated by an increase in lung wet to dry weight ratio, extravasation of plasma proteins and neutrophils into the bronchoalveolar lavage fluid, and an increase in total lung resistance. The increase in acute lung injury parameters in COCl2 (20 ppm, 10 min) exposed mice correlated with simultaneous increase in oxidation of red blood cells (RBC) membrane, RBC fragility, and plasma levels of cell-free heme. In addition, these mice had decreased plasmalogen levels (plasmenylethanolamine) and elevated levels of their breakdown product, polyunsaturated lysophosphatidylethanolamine, in the circulation suggesting damage to cellular plasma membranes. This study highlights the importance of free heme in the pathogenesis of COCl2 lung injury and identifies plasma membrane breakdown product as potential biomarkers of COCl2 toxicity.

Microvesicles (MVs) are important mediators of intercellular communication, packaging a variety of molecular cargo. They have been implicated in the pathophysiology of various inflammatory diseases; yet, their role in acute lung injury (ALI) remains unknown.

Optimization of intratracheal instillation is necessary to establish an ideal animal model of acute lung injury (ALI) in order to further reveal the cellular and molecular pathogenesis of ALI. It is possible that instilling air from a prefilled syringe may promote the delivery of reagents into the alveolar spaces, resulting in different pulmonary responses. In the present study, the influence of instilling air by trans-tracheal intratracheal instillation in a lipopolysaccharide (LPS)-induced mouse model of ALI was investigated. The bronchoalveolar lavage (BAL) fluid biochemical index, BAL fluid differential cell counts, lung wet/dry weight ratio, lung histology and BAL fluid interleukin-8 (IL-8) levels were assessed 24 h subsequent to intratracheal instillation. Instilled air promoted LPS-induced ALI, as indicated by the severity of acute pulmonary inflammation and increased IL-8 release. In conclusion, this study indicates that instilled air may be used to improve the intratracheal instillation procedure and to establish a more reliable animal model of ALI.