Animal models of acute lung injury

Medical Research Service of the Veterans Affairs/Puget Sound Health Care System, 815 Mercer St., Seattle, WA 98109, USA.
AJP Lung Cellular and Molecular Physiology (Impact Factor: 4.08). 08/2008; 295(3):L379-99. DOI: 10.1152/ajplung.00010.2008
Source: PubMed


Acute lung injury in humans is characterized histopathologically by neutrophilic alveolitis, injury of the alveolar epithelium and endothelium, hyaline membrane formation, and microvascular thrombi. Different animal models of experimental lung injury have been used to investigate mechanisms of lung injury. Most are based on reproducing in animals known risk factors for ARDS, such as sepsis, lipid embolism secondary to bone fracture, acid aspiration, ischemia-reperfusion of pulmonary or distal vascular beds, and other clinical risks. However, none of these models fully reproduces the features of human lung injury. The goal of this review is to summarize the strengths and weaknesses of existing models of lung injury. We review the specific features of human ARDS that should be modeled in experimental lung injury and then discuss specific characteristics of animal species that may affect the pulmonary host response to noxious stimuli. We emphasize those models of lung injury that are based on reproducing risk factors for human ARDS in animals and discuss the advantages and disadvantages of each model and the extent to which each model reproduces human ARDS. The present review will help guide investigators in the design and interpretation of animal studies of acute lung injury.

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    • "We speculate that this discrepancy is due, at least in part, to the fundamental differences between the presentation of ARDS in rodents and in man and the fact that most rat models do not use mechanical ventilation, which is a large component of ARDS pathogenesis [1] [2]. Rodent ARDS can be characterized as an " all-or-none " response, with the animal quickly transitioning from health to severe respiratory failure and death [12] [13]. Human ARDS, however, exhibits a wider spectrum of disease and a longer time-course [14]. "
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    ABSTRACT: Sepsis can lead to multiple organ dysfunction, including the Acute Respiratory Distress Syndrome (ARDS), due to intertwined, dynamic changes in inflammation and organ physiology. We have demonstrated the efficacy of Chemically-Modified Tetracycline 3 (CMT-3) at reducing inflammation and ameliorating pathophysiology in the setting of a clinically realistic porcine model of ARDS. Here, we sought to gain insights into the derangements that characterize sepsis/ARDS and the possible impact of CMT-3 thereon, by combined experimental and computational studies. Two groups of anesthetized, ventilated pigs were subjected to experimental sepsis via placement of a peritoneal fecal clot and intestinal ischemia/reperfusion by clamping the superior mesenteric artery for 30 min. The treatment group (n = 3) received CMT-3 at 1 hour after injury (T1), while the control group (n = 3) received a placebo. Multiple inflammatory mediators, along with clinically relevant physiologic and blood chemistry variables, were measured serially until death of the animal or T48. Principal Component Analysis (PCA) and Dynamic Bayesian Network (DBN) inference were used to relate these variables. PCA revealed a separation of cardiac and pulmonary physiologic variables by principal component, and a decreased rank of oxygen index and arterial PO 2 /FiO 2 ratio in the treatment group compared to control. DBN suggested a conserved network structure in both control and CMT-3 animals: a response driven by positive feedback between interleukin-6 and lung dysfunction. Resulting networks further suggested that in control animals, acute kidney injury, acidosis, and respiratory failure play an increased role in the response to insult compared to CMT-3 animals. These combined in vivo and in silico studies in a high fidelity, clinically applicable animal model suggest a dynamic interplay between inflammatory, physiologic, and blood chemistry variables in the setting of sepsis and ARDS that may be dramatically altered by pleiotropic interruption of inflammation by CMT-3. Introduction Acute respiratory distress syndrome (ARDS), with approximately 200,000 annual cases in the United States, is one of the leading causes of death in young adults and a major concern in victims of combat trauma in the military [1]. The accompanying cost for each case is roughly $150,000 [2]. The pathophysiology of ARDS causes death in 30-60% of affected patients, despite treatment with the standard of care low tidal volume (LTV) ventilation strategy [3]. Diagnostically, the principal feature of ARDS, according to the 2011 ESICM " Berlin " definition , is a PaO 2 /FiO 2 ratio of less than 300 mmHg. Additionally, respiratory symptoms must be new (< 1 week), lung imaging must indicate bilateral opacities, and alternative causes of acute hypoxemic respiratory failure must be ruled out. ARDS, resulting from heterogeneous etiologies, is a common endpoint of sepsis, hemorrhagic shock, and trauma. In the hospital setting,
    International Journal of Burns and Trauma 06/2015; 5(1):22-35.
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    • "Although supportive therapy has marginally improved survival of ALI/ARDS patients, effective therapeutic agents that improve clinical outcomes are urgently needed [1], [2]. LPS-induced lung injury is widely used as an experimental model to investigate the mechanisms of ALI [38]. Gaining a better understanding of the signaling pathways involved in this animal model may lead to novel insights and the identification of potential therapeutic targets. "
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    ABSTRACT: Background: Acute respiratory distress syndrome (ARDS) is a severe and life-threatening acute lung injury (ALI) that is caused by noxious stimuli and pathogens. ALI is characterized by marked acute inflammation with elevated alveolar cytokine levels. Mitogen-activated protein kinase (MAPK) pathways are involved in cytokine production, but the mechanisms that regulate these pathways remain poorly characterized. Here, we focused on the role of Sprouty-related EVH1-domain-containing protein (Spred)-2, a negative regulator of the Ras-Raf-extracellular signal-regulated kinase (ERK)-MAPK pathway, in lipopolysaccharide (LPS)-induced acute lung inflammation. Methods: Wild-type (WT) mice and Spred-2(-/-) mice were exposed to intratracheal LPS (50 µg in 50 µL PBS) to induce pulmonary inflammation. After LPS-injection, the lungs were harvested to assess leukocyte infiltration, cytokine and chemokine production, ERK-MAPK activation and immunopathology. For ex vivo experiments, alveolar macrophages were harvested from untreated WT and Spred-2(-/-) mice and stimulated with LPS. In in vitro experiments, specific knock down of Spred-2 by siRNA or overexpression of Spred-2 by transfection with a plasmid encoding the Spred-2 sense sequence was introduced into murine RAW264.7 macrophage cells or MLE-12 lung epithelial cells. Results: LPS-induced acute lung inflammation was significantly exacerbated in Spred-2(-/-) mice compared with WT mice, as indicated by the numbers of infiltrating leukocytes, levels of alveolar TNF-α, CXCL2 and CCL2 in a later phase, and lung pathology. U0126, a selective MEK/ERK inhibitor, reduced the augmented LPS-induced inflammation in Spred-2(-/-) mice. Specific knock down of Spred-2 augmented LPS-induced cytokine and chemokine responses in RAW264.7 cells and MLE-12 cells, whereas Spred-2 overexpression decreased this response in RAW264.7 cells. Conclusions: The ERK-MAPK pathway is involved in LPS-induced acute lung inflammation. Spred-2 controls the development of LPS-induced lung inflammation by negatively regulating the ERK-MAPK pathway. Thus, Spred-2 may represent a therapeutic target for the treatment of ALI.
    PLoS ONE 10/2014; 9(10):e108914. DOI:10.1371/journal.pone.0108914 · 3.23 Impact Factor
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    • "These findings are in accord with a randomized controlled clinical study on PTE, lung transplantation and the mechanisms [30,42]. The mechanisms of injury may involve neutrophil activation, oxygen radicals, cytokines, complement, arachidonic acid derivatives, platelet activating factor [43]. The LIRI can be effectively blunted by the reduction of macrophage-dependent injury by gadolinium while inhaled NO also will attenuate injury by reducing pulmonary hypertension and minimizing neutrophil sequestration [44]. "
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    ABSTRACT: Background Lung ischemia–reperfusion injury (LIRI) may occur in the region of the affected lung after reperfusion therapy. Inhaled NO may be useful in treating acute and chronic pulmonary thromboembolism (PTE) due to the biological effect property of NO. Methods A PTE canine model was established through selectively embolizing blood clots to an intended right lower lobar pulmonary artery. PaO2/FiO2, the mPAP and PVR were investigated at the time points of 2, 4, 6 hours after inhaled NO. Masson’s trichrome stain, apoptotic pneumocytes and lung sample ultrastructure were also investigated among different groups. Results The PaO2/FiO2 in the Inhaled NO group increased significantly when compared with the Reperfusion group at time points of 4 and 6 hours after reperfusion, mPAP decreased significantly at point of 2 hours and the PVR decreased significantly at point of 6 hours after reperfusion. The amounts of apoptotic type II pneumocytes in the lower lobar lung have negative correlation trend with the arterial blood PaO2/FiO2 in Reperfusion group and Inhaled NO group. Inhaled nitric oxide given at 20 ppm for 6 hours can significantly alleviate the LIRI in the model. Conclusions Dramatic physiological improvements are seen during the therapeutic use of inhaled NO in pulmonary thromboembolism canine model. Inhaled NO may be useful in treating LIRI in acute or chronic PTE by alleviating apoptotic type II pneumocytes. This potential application warrants further investigation.
    Theoretical Biology and Medical Modelling 08/2014; 11(1):36. DOI:10.1186/1742-4682-11-36 · 0.95 Impact Factor
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