Pulmonary Macrophage Inhibition and Inhaled Nitric Oxide Attenuate Lung Ischemia-Reperfusion Injury

Gazoni, Leo M.; Tribble, Curtis G.; Zhao, Min; Unger, Eric B.; Farrar, Robert A.; Ellman, Peter I.; Fernández, Lucas G.; Laubach, Victor E.; Krön, Irving L.

doi:10.1016/j.athoracsur.2007.02.036

Cited by 24 publications

(19 citation statements)

References 32 publications

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“…This AM-dependent oxidant stress is thought to contribute importantly to septic ALI (8,20). Indeed, infusion of gadolinium chloride, an inhibitor of macrophage activation (38), has been shown to abrogate ALI (19,35,41). Lipid peroxidation has been suggested as a contributory mechanism of ALI (2), since both animal and clinical studies have shown increased lipid peroxidation products in lung tissue in ALI (23,24,44).…”

Section: Discussionmentioning

confidence: 98%

Septic pulmonary microvascular endothelial cell injury: role of alveolar macrophage NADPH oxidase

Farley¹,

Wang²,

Mehta³

2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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A significant role for alveolar macrophages (AM) in the pathophysiology of sepsis-induced acute lung injury (ALI) has been shown; however, the mechanisms behind AM-related lung injury remain relatively uncertain. We examined the role of AM nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in pulmonary endothelial cell septic injury. NADPH oxidase is one of the major sources of cellular reactive oxygen species and has been implicated in endothelial injury in ALI. Pulmonary microvascular endothelial cells (PMVEC) monolayers were grown on Transwell inserts and incubated with wild-type and NADPH oxidase-deficient AM in the presence or absence of cytomix (equimolar TNF-alpha, IL-1beta, and IFN-gamma). Injury to the monolayers was assessed by trans-PMVEC Evans blue (EB)-labeled albumin flux. We found AM under cytomix stimulation caused significant EB-albumin flux across the PMVEC monolayers, and this effect was attenuated by the genetic deletion of AM NADPH oxidase. The pharmacological inhibition of AM NADPH oxidase with apocynin and PR-39 also significantly reduced AM-dependent PMVEC injury. In the AM-PMVEC cocultures, we also assessed PMVEC injury through measurement of protein oxidation and lipid peroxidation. AM were shown to cause a significant increase in these markers of PMVEC injury, which was also attenuated by the inhibition of NADPH oxidase or through the use of NADPH oxidase-deficient AM. PMVEC NADPH oxidase was shown not to significantly contribute to PMVEC injury in our studies. From our findings we have concluded that AM NADPH oxidase is crucial for the septic increase in pulmonary vascular permeability.

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Section: Discussionmentioning

confidence: 98%

Septic pulmonary microvascular endothelial cell injury: role of alveolar macrophage NADPH oxidase

Farley¹,

Wang²,

Mehta³

2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Compelling evidence has shown that inflammatory responses mediate lung IR injury (9,(22)(23)(24). ROS have been suggested to be a critical component of this inflammatory response possibly as both a mediator and an end effector.…”

Section: Discussionmentioning

confidence: 99%

NADPH Oxidase in Bone Marrow–Derived Cells Mediates Pulmonary Ischemia-Reperfusion Injury

Yang¹,

Sharma²,

Marshall³

et al. 2009

Am J Respir Cell Mol Biol

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Reactive oxygen species (ROS) play a crucial role in ischemiareperfusion (IR) injury after lung transplantation. We hypothesized that NADPH oxidase derived from bone marrow (BM) cells contributes importantly to lung IR injury. An in vivo mouse model of lung IR injury was employed. Wild-type C57BL/6 (WT) mice, p47 phox knockout (p47 phox 2/2) mice, or chimeras created by BM transplantation between WT and p47 phox 2/2 mice were assigned to either Sham (left thoracotomy) or six study groups that underwent IR (1 h left hilar occlusion and 2 h reperfusion). After reperfusion, pulmonary function was assessed using an isolated, buffer-perfused lung system. Lung injury was assessed by measuring vascular permeability (via Evans blue dye), edema, neutrophil infiltration (via myeloperoxidase [MPO]), lipid peroxidation (via malondialdyhyde [MDA]), and expression of proinflammatory cytokines. Lung IR resulted in significantly increased MDA in WT mice, indicative of oxidative stress. WT mice treated with apocynin (an NADPH oxidase inhibitor) and p47 phox 2/2 mice displayed significantly reduced pulmonary dysfunction and injury (vascular permeability, edema, MPO, and MDA). In BM chimeras, significantly reduced pulmonary dysfunction and injury occurred after IR in p47 phox 2/2/WT chimeras (donor/recipient) but not WT/p47 phox 2/2 chimeras. Induction of TNF-a, IL-17, IL-6, RANTES (CCL5), KC (CXCL1), MIP-2 (CXCL2), and MCP-1 (CCL2) was significantly reduced after IR in NADPH oxidase-deficient mice and p47 phox 2/2/WT chimeras but not WT/p47 phox 2/2 chimeras. These results indicate that NADPH oxidase-generated ROS specifically from BM-derived cells contributes importantly to lung IR injury. NADPH oxidase may represent a novel therapeutic target for the treatment of IR injury after lung transplantation.

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“…The neutrophil chemokine CXCL1 (also known as CINC-1) and its receptor, CXCR1, were greatly increased by bleomycin but were unaffected by exposure to 7% CO 2 (Table 3). TNF-␣, a proinflammatory cytokine that may recruit macrophages to the lung (18,46) or be tissue macrophage derived (59), was increased in bleomycin-exposed lungs and was normalized by concurrent exposure to 7% CO 2 (Table 3). Similar to findings in qPCR, lung TNF-␣ protein content was significantly (P Ͻ 0.05) increased by treatment with bleomycin and completely normalized by exposure to 7%, but not by 5%, CO 2 (Fig.…”

Section: Changes In Distal Airway Morphology Secondary To Bleomycinmentioning

confidence: 99%

Therapeutic hypercapnia prevents bleomycin-induced pulmonary hypertension in neonatal rats by limiting macrophage-derived tumor necrosis factor-α

Sewing

Kantores

Ivanovska

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Sewing AC, Kantores C, Ivanovska J, Lee AH, Masood A, Jain A, McNamara PJ, Tanswell AK, Jankov RP. Therapeutic hypercapnia prevents bleomycin-induced pulmonary hypertension in neonatal rats by limiting macrophage-derived tumor necrosis factor-␣. Am J Physiol Lung Cell Mol Physiol 303: L75-L87, 2012. First published May 11, 2012; doi:10.1152/ajplung.00072.2012.-Bleomycin-induced lung injury is characterized in the neonatal rat by inflammation, arrested lung growth, and pulmonary hypertension (PHT), as observed in human infants with severe bronchopulmonary dysplasia. Inhalation of CO2 (therapeutic hypercapnia) has been described to limit cytokine production and to have anti-inflammatory effects on the injured lung; we therefore hypothesized that therapeutic hypercapnia would prevent bleomycin-induced lung injury. Spontaneously breathing rat pups were treated with bleomycin (1 mg/kg/d ip) or saline vehicle from postnatal days 1-14 while being continuously exposed to 5% CO2 (PaCO 2 elevated by 15-20 mmHg), 7% CO2 (PaCO 2 elevated by 35 mmHg), or normocapnia. Bleomycin-treated animals exposed to 7%, but not 5%, CO2, had significantly attenuated lung tissue macrophage influx and PHT, as evidenced by normalized pulmonary vascular resistance and right ventricular systolic function, decreased right ventricular hypertrophy, and attenuated remodeling of pulmonary resistance arteries. The level of CO2 neither prevented increased tissue neutrophil influx nor led to improvements in decreased lung weight, septal thinning, impaired alveolarization, or decreased numbers of peripheral arteries. Bleomycin led to increased expression and content of lung tumor necrosis factor (TNF)-␣, which was found to colocalize with tissue macrophages and to be attenuated by exposure to 7% CO2. Inhibition of TNF-␣ signaling with the soluble TNF-2 receptor etanercept (0.4 mg/kg ip from days 1-14 on alternate days) prevented bleomycin-induced PHT without decreasing tissue macrophages and, similar to CO2, had no effect on arrested alveolar development. Our findings are consistent with a preventive effect of therapeutic hypercapnia with 7% CO2 on bleomycin-induced PHT via attenuation of macrophage-derived TNF-␣. Neither tissue macrophages nor TNF-␣ appeared to contribute to arrested lung development induced by bleomycin. That 7% CO2 normalized pulmonary vascular resistance and right ventricular function without improving inhibited airway and vascular development suggests that vascular hypoplasia does not contribute significantly to functional changes of PHT in this model. carbon dioxide; inflammation; neonatal lung injury BRONCHOPULMONARY DYSPLASIA (BPD) is a chronic pneumopathy affecting extremely premature infants who frequently require supplemental oxygen and/or mechanical ventilation. The incidence of BPD is inversely proportional to the gestational age at which infants are born, with an incidence approaching 60% in the smallest survivors (4). The cardinal feature of BPD, as observed in the current era, is an inhibition or arrest of alveolar and ...

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Pulmonary Macrophage Inhibition and Inhaled Nitric Oxide Attenuate Lung Ischemia-Reperfusion Injury

Cited by 24 publications

References 32 publications

Septic pulmonary microvascular endothelial cell injury: role of alveolar macrophage NADPH oxidase

Septic pulmonary microvascular endothelial cell injury: role of alveolar macrophage NADPH oxidase

NADPH Oxidase in Bone Marrow–Derived Cells Mediates Pulmonary Ischemia-Reperfusion Injury

Therapeutic hypercapnia prevents bleomycin-induced pulmonary hypertension in neonatal rats by limiting macrophage-derived tumor necrosis factor-α

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