Independent and Combined Effects of Prolonged Inhaled Nitric Oxide and Oxygen on Lung Inflammation in Newborn Piglets

Ekekezie, Ikechukwu I; Thibeault, Donald W.; Zwick, David L.; Rezaiekhaligh, Mohammad H.; Mabry, Sherry M; Morgan, Ruth; Norberg, Michael; Truog, William E.

doi:10.1159/000014193

Cited by 27 publications

(14 citation statements)

References 36 publications

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“…Additionally, we hypothesized that lung CCR-2 will show a similar trend. We used a young piglet model (20) characterized by rapidly growing lungs to assess lung MCP-1 production and CCR-2 and leukocyte dynamics after 1 and 5 d of separate or concurrent exposure to NO and hyperoxia.…”

mentioning

confidence: 99%

Monocyte Chemoattractant Protein-1 and Its Receptor CCR-2 in Piglet Lungs Exposed to Inhaled Nitric Oxide and Hyperoxia

et al. 2001

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Monocyte chemoattractant protein-1 (MCP-1), acting through its C-C chemokine receptor 2 (CCR-2), has important roles in inflammation, angiogenesis, and wound repair. The individual and combined effects of inhaled nitric oxide (NO) and hyperoxia on lung MCP-1 and CCR-2 in relation to lung leukocyte dynamics are unknown. Because MCP-1 gene is up-regulated by oxidants, we hypothesized that inhaled NO with hyperoxia will increase MCP-1 production and CCR-2 expression more than either gas alone. We randomly assigned young piglets to breathe room air (RA), RAϩ50 ppm NO (RAϩNO), O 2 , or O 2 ϩNO for 1 or 5 d before sacrifice. Lungs were lavaged and tissues preserved for hybridization studies, Western blotting, histology, and immunohistochemistry. The results show that lung MCP-1 production and alveolar macrophage count were significantly elevated in the 5-d O 2 and O 2 ϩNO groups relative to the RA group (p Յ 0.05). In contrast, lung CCR-2 abundance was diminished in the O 2 group (p Յ 0.05), but not in the O 2 ϩNO group, compared with the RA group. No difference was detected in any variable studied at 24 h. CCR-2 distribution was similar in all groups with staining of alveolar septa, macrophages, vascular endothelium, and the luminal epithelial surface of airways. We conclude that although hyperoxia increases MCP-1 in young piglet lungs, it also decreases CCR-2 abundance, which may limit participation of MCP-1 in alveolar macrophage recruitment. Inhaled NO, unlike hyperoxia, has no significant independent effect, but its concurrent administration during hyperoxia attenuates the decremental effect of hyperoxia on CCR-2 abundance. Abbreviations MCP-1, monocyte chemoattractant protein-1 NO, nitric oxide MPO, myeloperoxidase CCR-2, C-C chemokine receptor 2 RA, room air RPA, ribonuclease protection assay Animals exposed to prolonged hyperoxia suffer lung injury from pulmonary sequestration of activated leukocytes, which release cytokines, reactive oxygen species, and tissuedegrading enzymes (1-3). The leukocyte influx is orchestrated and amplified by chemotactic factors (1-4).In the early phase, neutrophil accumulation predominates, but this pattern changes to one of monocytes/macrophages beyond 72 h (3). The change in the inflammatory cell composition results from proliferation of resident alveolar macrophages as well as pulmonary transmicrovascular migration of blood monocytes (1, 3). The factors controlling these later events are not fully understood, but known proinflammatory cytokines may be involved.MCP-1 is a C-C chemokine with activating and chemoattractant actions on monocytes and macrophages (5). In addition to its chemoattractant characteristics, MCP-1 also induces mesothelial, fibroblast, endothelial, and vascular smooth muscle cell proliferation and migration (6 -9). MCP-1 is produced by various immune and nonimmune cell types including alveolar macrophages (5).The actions of MCP-1 are mediated primarily through CCR-2 (10). These receptors are now known to be expressed by mesothelial, fibroblasts, and endothel...

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confidence: 99%

Monocyte Chemoattractant Protein-1 and Its Receptor CCR-2 in Piglet Lungs Exposed to Inhaled Nitric Oxide and Hyperoxia

et al. 2001

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“…However, studies have shown that prolonged exposure to the combination of NO and hyperoxia (NO/O 2 ) causes significantly more lung injury than hyperoxia alone in several animal models, including piglets (1) and rats (2). This increased lung injury is associated with increased apoptosis of lung cells (3). We have previously shown that exposure of cultured pulmonary cells to NO and hyperoxia causes a synergistic cytotoxicity (4), similar to that observed in lungs of exposed animals.…”

Section: Inhaled Nitric Oxide (Ino)mentioning

confidence: 79%

Suppression of Nuclear Factor-κB Activity by Nitric Oxide and Hyperoxia in Oxygen-resistant Cells

Franek

Chowdary

Lin

et al. 2002

Journal of Biological Chemistry

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Inhaled nitric oxide (iNO) is used clinically to treat pulmonary hypertension in newborns, often in conjunction with hyperoxia (NO/O 2 ). Prolonged exposure to NO/O 2 causes synergistic lung injury and death of lung epithelial cells. To explore the mechanisms involved, oxygen-resistant HeLa-80 cells were exposed to NO ؎ O 2 . Exposure to NO and O 2 induced a synergistic cytotoxicity, accompanied with apoptotic characteristics, including elevated caspase-3-like activity, Annexin V incorporation, and nuclear condensation. This apoptosis was associated with a synergistic suppression of NF-B activity. Cells lacking functional NF-B p65 subunit were more sensitive to NO/O 2 than their wild type counterparts. This injury was partially rescued by transfection with a p65 expression construct, suggesting an inverse relationship between NF-B and susceptibility to the cytotoxicity of NO/O 2 . Despite the reduced NF-B activity in cells exposed to NO ؎ O 2 , IB␣ was degraded, suggesting that pathways regulating the steady-state levels of IB were not involved. However, exposure to NO/O 2 caused a marked reduction in nuclear localization and an increase in protein carbonyl formation of NF-B p65 subunit. These results suggest that NO/O 2 -induced apoptosis occurs by suppressing NF-B activity. Inhaled nitric oxide (iNO)1 is used clinically as a therapeutic modality to selectively manipulate the pulmonary vasculature for the treatment of persistent pulmonary hypertension of the newborn. In most cases, these patients receive simultaneous oxygen therapy with supraphysiological concentrations of oxygen. However, studies have shown that prolonged exposure to the combination of NO and hyperoxia (NO/O 2 ) causes significantly more lung injury than hyperoxia alone in several animal models, including piglets (1) and rats (2). This increased lung injury is associated with increased apoptosis of lung cells (3). We have previously shown that exposure of cultured pulmonary cells to NO and hyperoxia causes a synergistic cytotoxicity (4), similar to that observed in lungs of exposed animals. In addition, significantly more apoptosis has been found when isolated human neutrophils and primary cultures of normal human lung fibroblasts were exposed to NO/O 2 than those exposed to O 2 alone (5, 6). These studies suggest that prolonged exposure to the combination of NO and hyperoxia has direct toxic effects on lung cells and the resulting injury and death of pulmonary cells may lead to impaired pulmonary function and lung injury.NF-B is a key redox-sensitive transcription factor in inflammatory diseases, where it regulates the inflammatory response by modulating the gene expression of cytokines, chemokines, and adhesion molecules (7,8). In addition, NF-B has been shown to play a pivotal role in mediating cell proliferation and survival against a variety of cell death stimuli, including oxidative and nitrosative stress (9 -15). NO has also been shown to be closely associated with NF-B. NF-B is an essential transcription factor for the production of en...

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“…The animal exposure method has been reported previously (13,37). Briefly, we randomly separated 10-to 17-d-old piglets into three groups and placed them for 5 d in chambers that contained 1) room air (RA), 2) Ͼ95% oxygen (O 2 ), or 3) O 2 ϩ 50 ppm of NO (O 2 ϩ NO).…”

Section: Methodsmentioning

confidence: 99%

“…Hyperoxic damage to the lung is accompanied by inflammatory reactions such as leukocyte infiltration and cytokine release into the lung parenchyma (13). PDGF may be involved in this process because of its chemotactic and stimulatory effects to neutrophils and monocytes (14,15).…”

mentioning

confidence: 99%

Responses of Pulmonary Platelet-Derived Growth Factor Peptides and Receptors to Hyperoxia and Nitric Oxide in Piglet Lungs

et al. 2005

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Independent and Combined Effects of Prolonged Inhaled Nitric Oxide and Oxygen on Lung Inflammation in Newborn Piglets

Cited by 27 publications

References 36 publications

Monocyte Chemoattractant Protein-1 and Its Receptor CCR-2 in Piglet Lungs Exposed to Inhaled Nitric Oxide and Hyperoxia

Monocyte Chemoattractant Protein-1 and Its Receptor CCR-2 in Piglet Lungs Exposed to Inhaled Nitric Oxide and Hyperoxia

Suppression of Nuclear Factor-κB Activity by Nitric Oxide and Hyperoxia in Oxygen-resistant Cells

Responses of Pulmonary Platelet-Derived Growth Factor Peptides and Receptors to Hyperoxia and Nitric Oxide in Piglet Lungs

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