Effects of heparin and lisofylline on pulmonary function after smoke inhalation injury in an ovine model*

Tasaki, Osamu; Mozingo, D.W.; Dubick, Michael A.; Goodwin, Cleon W.; Yantis, Loudon D.; Pruitt, Basil A.

doi:10.1097/00003246-200203000-00024

Cited by 47 publications

(28 citation statements)

References 26 publications

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“…In fact cholesterols, elevated to the levels measured in the airways of subjects with ALI (14,44), more prominently inhibit the surface tension lowering effects of surfactant in vitro than do serum proteins (21), a disparity that could also apply in vivo. With this in mind, it is curious to note that most studies reporting improved lung function with the use of fibrinolytic agents in ALI have focused predominantly on ventilationperfusion matching and oxygenation (2,16,50,57), with limited reporting on changes in lung mechanical function. The one study reporting a reduction in peak airway pressures following aerosolized tPA used a sheep model of burn and smoke inhalation injury (16), a model characterized by extensive obstruction of large and small airways with fibrinous debris (16).…”

Section: Discussionmentioning

confidence: 99%

Neither fibrin nor plasminogen activator inhibitor-1 deficiency protects lung function in a mouse model of acute lung injury

Allen

Cloutier²,

Larrabee³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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Allen GB, Cloutier ME, Larrabee YC, Tetenev K, Smiley ST, Bates JH. Neither fibrin nor plasminogen activator inhibitor-1 deficiency protects lung function in a mouse model of acute lung injury. Am J Physiol Lung Cell Mol Physiol 296: L277-L285, 2009. First published December 5, 2008 doi:10.1152/ajplung.90475.2008.-Fibrin impairs surfactant function in vitro, and inhibition of fibrinolysis by plasminogen activator inhibitor (PAI-1) is thought to promote fibrin accumulation in acute lung injury (ALI). This has led to speculation that impaired PAI-1 and fibrin accumulation should protect lung function in ALI. We tested this hypothesis by investigating ALI severity in fibrinogen-deficient (FgnϪ/Ϫ) and PAI-1-deficient (PAI-1Ϫ/Ϫ) mice. PAI-1Ϫ/Ϫ, C57BL/6, FgnϪ/Ϫ, and Fgnϩ/Ϫ females were anesthetized and allowed to aspirate 4 l/g of hydrochloric acid (pH 1.0) and then reanesthetized and connected to a ventilator 48 h later. Naive C57BL/6 and Fgnϩ/Ϫ females served as controls. Following deep inflation (DI), forced oscillations were delivered periodically over 8 min to measure changes in elastance (H) as a surrogate of lung derecruitment, at positive end-expiratory pressures (PEEP) of 6, 3, and 1 cmH 2O. Increases in H following DI in acid-injured mice were greater than naive strain-matched controls. Increases in H were no different between injured PAI-1Ϫ/Ϫ and C57BL/6, or between injured FgnϪ/Ϫ and ϩ/Ϫ mice, at any PEEP. Pressure-volume curves were no different between injured groups. Total lung fibrin was lower in injured PAI-1Ϫ/Ϫ and FgnϪ/Ϫ mice relative to injured C57BL/6 and Fgnϩ/Ϫ mice, respectively, but indices of permeability were no different between strains. Unexpectedly, neither fibrin nor PAI-1 deficiency protects lung mechanical function in mice with acid-induced ALI. We speculate that in vivo lung function may be more closely tied to permeability and alveolar protein in general, rather than being linked specifically to fibrin. lung mechanics; respiratory impedance; acid aspiration; coagulation ACUTE LUNG INJURY (ALI) is a severe form of noncardiogenic pulmonary edema and hypoxemic respiratory failure stemming from numerous causes (60). Current treatment of ALI rests largely on supportive care with mechanical ventilation, and its prognosis remains poor with a mortality of 30 -40% in the general population, and higher in the elderly (49). The pathology of ALI typically progresses through an initial exudative phase characterized by neutrophil infiltration, edema, and accumulation of hyaline membranes, the latter consisting primarily of necrotic debris and fibrin (58). In this regard, the coagulation pathway and its end product fibrin have excited particular interest, in part due to the ability of fibrin to inhibit surfactant function in vitro (52,54), and the increasingly recognized interplay between coagulation and innate immunity (17,63). Fibrin formation and clearance in the lung are governed by the relative quantity and activity of fibrinolysis promoters such as plasminogen activators and fibrinolysis inh...

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Section: Discussionmentioning

confidence: 99%

Neither fibrin nor plasminogen activator inhibitor-1 deficiency protects lung function in a mouse model of acute lung injury

Allen

Cloutier²,

Larrabee³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…An effect of nebulized heparin on systemic coagulation was reported in one study using a lung injury model (49), but not in studies using pulmonary infection models (36,49) or inhalation trauma models (38)(39)(40)(41)(42). None of these studies, however, showed systemic bleeding.…”

Section: Heparinmentioning

confidence: 98%

“…Nebulized heparin also affected various physiologic parameters and other outcomes, in particular during pulmonary infection (34,35), and inhalation trauma (38)(39)(40)(41)(42)). An effect of nebulized heparin on systemic coagulation was reported in one study using a lung injury model (49), but not in studies using pulmonary infection models (36,49) or inhalation trauma models (38)(39)(40)(41)(42).…”

Section: Heparinmentioning

confidence: 99%

“…Notably, combination of both anticoagulants resulted in more pronounced attenuation of inflammatory and physiological parameters than treatment with one agent alone. Combining nebulized heparin with intravenously administered AT markedly decreased pulmonary inflammation and improved physiological parameters in a study of inhalation trauma (41), while combining nebulized heparin with intravenously administered lisofylline improved physiological parameters, but inflammation in a study using a similar model (39). Combining nebulized heparin with nebulized tissue plasminogen activator (TPA) and intravenously administered AT did not affect inflammation, but also significantly improved physiological parameters in a study of inhalation trauma (42).…”

Section: Combination Therapy Using More Than One Anticoagulantmentioning

confidence: 99%

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Nebulized anticoagulants in lung injury in critically ill patients—an updated systematic review of preclinical and clinical studies

et al. 2017

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Pneumonia, inhalation trauma and acute respiratory distress syndrome (ARDS), typical causes of lung injury in critically ill patients, are all three characterized by dysregulated inflammation and coagulation in the lungs. Nebulized anticoagulants are thought to have beneficial effects as they could attenuate pulmonary coagulopathy and maybe even affect pulmonary inflammation. A systematic search of the medical literature was performed using terms referring to aspects of the condition ('pneumonia', 'inhalation trauma' and 'ARDS'), the intervention ('nebulized', 'vaporized', and 'aerosolized') and anticoagulants limited to agents that are commercially available and frequently given or tested in critically ill patients ['heparin', 'danaparoid', 'activated protein C' (APC), 'antithrombin' (AT) and 'tissue factor pathway inhibitor' (TFPI)].The systematic search identified 16 articles reporting on preclinical studies and 11 articles reporting on human trials. All nebulized anticoagulants attenuate pulmonary coagulopathy in preclinical studies using various models for lung injury, but the effects on inflammation are less consistent. Nebulized heparin, danaparoid and TFPI, but not APC and AT also reduced systemic coagulation. Nebulized heparin in lung injury patients shows contradictory results, and there is concern over systemic side effects of this strategy.Future studies need to focus on the way to nebulize anticoagulants, as well as on efficient but safe dosages, and other side effects.

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“…These include antiadherence agents (blocking neutrophil adherence in the pulmonary microvasculature), leukotriene inhibitors, inhaled heparin, and antioxidants (42)(43)(44) , although controlled clinical studies are still necessary before these new treatment alternatives can be adopted in clinical practice.…”

Section: Therapeutic Perspectivesmentioning

confidence: 99%

Lesão por inalação de fumaça

Souza¹,

Jardim²,

Salge³

et al. 2004

J. bras. pneumol.

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Inhalation injury is the main cause of death in burn patients and has therefore, understandably, been the subject of numerous published studies. The pathogenesis of inhalation injury involves both local and systemic mechanisms, thereby increasing the repercussions of the injury. The search for tools that would allow earlier diagnosis of inhalation injury and for treatment strategies to lessen its deleterious effects is ongoing. In this review, we describe the physiopathological mechanisms of inhalation injury, as well as the current diagnostic tools and treatment strategies used in patients suffering from inhalation injury. We also attempt to put experimental therapeutic approaches into perspective.

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Effects of heparin and lisofylline on pulmonary function after smoke inhalation injury in an ovine model*

Cited by 47 publications

References 26 publications

Neither fibrin nor plasminogen activator inhibitor-1 deficiency protects lung function in a mouse model of acute lung injury

Neither fibrin nor plasminogen activator inhibitor-1 deficiency protects lung function in a mouse model of acute lung injury

Nebulized anticoagulants in lung injury in critically ill patients—an updated systematic review of preclinical and clinical studies

Lesão por inalação de fumaça

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