Monocyte Chemoattractant Protein–1 Released from Alveolar Macrophages Mediates the Systemic Inflammation of Acute Alveolar Hypoxia

Chao, Jie; Donham, Paula; Rooijen, Nico van; Wood, John G.; González, Norberto C.

doi:10.1165/rcmb.2010-0264oc

Cited by 52 publications

(70 citation statements)

References 48 publications

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“…(4,5). 3) Plasma MCP-1 concentration increases rapidly in rats breathing 10% O 2 ; this increase does not occur in AMO-depleted rats (4). This is consistent with previous observations that AMO depletion prevents the systemic inflammation of alveolar hypoxia and that plasma from intact hypoxic rats, but not of AMO-depleted rats, elicits inflammation in normoxic tissues (5,9).…”

supporting

confidence: 88%

“…(4,5). 3) Plasma MCP-1 concentration increases rapidly in rats breathing 10% O 2 ; this increase does not occur in AMO-depleted rats (4).…”

mentioning

confidence: 94%

“…5) MCP-1 induces concentration-dependent MC degranulation (4). 6) MCP-1 administration to normoxic rats replicates the inflammation of hypoxia; conversely, MCP-1 receptor antagonist blocks the systemic inflammation of hypoxia in intact rats (4).…”

mentioning

confidence: 97%

“…This response, which has been observed directly in the mesentery (4, 5, 22, 30 -32) and skeletal muscle (6,10,21) and pial microcirculations (13), is not initiated by the low tissue PO 2 but rather by the rapid release into the circulation of a chemokine, monocyte chemoattractant protein-1 (MCP-1), also known as CCL2, from alveolar macrophages (AMO) activated by the low alveolar PO 2 (4). Circulating MCP-1 induces degranulation of perivascular MCs (4), which, in turn, leads to activation of the reninangiotensin system (RAS) and microvascular inflammation (10).…”

mentioning

confidence: 99%

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Renin released from mast cells activated by circulating MCP-1 initiates the microvascular phase of the systemic inflammation of alveolar hypoxia

Chao¹,

Blanco²,

Wood

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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NC. Renin released from mast cells activated by circulating MCP-1 initiates the microvascular phase of the systemic inflammation of alveolar hypoxia. Am J Physiol Heart Circ Physiol 301: H2264 -H2270, 2011. First published September 30, 2011; doi:10.1152/ajpheart.00461.2011.-Reduced alveolar PO 2 in rats produces a rapid systemic inflammation characterized by reactive O 2 species generation, mast cell (MC) degranulation, leukocyte-endothelial interactions, and increased vascular permeability. The inflammation is not initiated by the low systemic PO 2 but rather by the release of monocyte chemoattractant protein-1 (MCP-1) from alveolar macrophages (AMO) activated by alveolar hypoxia. Circulating AMO-borne MCP-1 induces MC degranulation, which activates the local renin-angiotensin system (RAS) and mediates the microvascular inflammation. This study was directed to determine the mechanism of RAS activation by MCP-1-induced MC degranulation. Experiments in isolated rat peritoneal MCs showed the following: 1) Western blots and immunocytochemistry demonstrated the presence of renin and angiotensin-converting enzyme (ACE) in MCs and their release upon degranulation; 2) MCP-1-induced degranulation of MCs incubated in plasma produced an increase in angiotensin II (ANG II) concentration; and 3) this increase was inhibited completely by the following agents: the MCP-1 receptor antagonist RS-102895, the specific rat renin inhibitor WFML, or the ACE inhibitor captopril administered separately. Captopril also inhibited ANG II generation by MCs incubated in culture medium plus ANG I. The results show that peritoneal MCs contain active renin, which activates the RAS upon degranulation, and that peritoneal MCs are a source of ACE and suggest that conversion of ANG I to ANG II is mediated predominantly by ACE. This study provides novel evidence of the presence of active renin in rat peritoneal MCs and helps explain the mechanism of activation of the RAS during alveolar hypoxia. monocyte chemoattractant protein-1; angiotensin-converting enzyme REDUCTION OF INSPIRED PO 2 in rats produces a rapid and widespread systemic inflammation characterized by microvascular generation of reactive O 2 species (30), mast cell (MC) degranulation (22), increased leukocyte-endothelial interactions (31), and extravasation of albumin (32). This response, which has been observed directly in the mesentery (4, 5, 22, 30 -32) and skeletal muscle (6, 10, 21) and pial microcirculations (13), is not initiated by the low tissue PO 2 but rather by the rapid release into the circulation of a chemokine, monocyte chemoattractant protein-1 (MCP-1), also known as CCL2, from alveolar macrophages (AMO) activated by the low alveolar PO 2 (4). Circulating MCP-1 induces degranulation of perivascular MCs (4), which, in turn, leads to activation of the reninangiotensin system (RAS) and microvascular inflammation (10).The possibility that the systemic inflammation is initiated by a mediator released from a distant site and transported by blood had been suggested by two c...

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supporting

confidence: 88%

“…(4,5). 3) Plasma MCP-1 concentration increases rapidly in rats breathing 10% O 2 ; this increase does not occur in AMO-depleted rats (4).…”

mentioning

confidence: 94%

mentioning

confidence: 97%

mentioning

confidence: 99%

See 2 more Smart Citations

Renin released from mast cells activated by circulating MCP-1 initiates the microvascular phase of the systemic inflammation of alveolar hypoxia

Chao¹,

Blanco²,

Wood

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

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“…Our findings identify AMs as the prominent source of CCL-2 production in LC. In response to conditions like hypoxia, CCL-2 can act as a mediator of the systemic inflammatory response elicited by macrophages (36).…”

Section: Discussionmentioning

confidence: 99%

Role of Macrophage Chemoattractant Protein-1 in Acute Inflammation after Lung Contusion

Suresh

Machado-Aranda

et al. 2012

Am J Respir Cell Mol Biol

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Lung contusion (LC), commonly observed in patients with thoracic trauma is a leading risk factor for development of acute lung injury/ acute respiratory distress syndrome. Previously, we have shown that CC chemokine ligand (CCL)-2, a monotactic chemokine abundant in the lungs, is significantly elevated in LC. This study investigated the nature of protection afforded by CCL-2 in acute lung injury/acute respiratory distress syndrome during LC, using rats and CC chemokine receptor (CCR) 2 knockout (CCR2 2/2 ) mice. Rats injected with a polyclonal antibody to CCL-2 showed higher levels of albumin and IL-6 in the bronchoalveolar lavage and myeloperoxidase in the lung tissue after LC. Closed-chest bilateral LC demonstrated CCL-2 localization in alveolar macrophages (AMs) and epithelial cells. Subsequent experiments performed using a murine model of LC showed that the extent of injury, assessed by pulmonary compliance and albumin levels in the bronchoalveolar lavage, was higher in the CCR2 2/2 mice when compared with the wild-type (WT) mice. We also found increased release of IL-1b, IL-6, macrophage inflammatory protein-1, and keratinocyte chemoattractant, lower recruitment of AMs, and higher neutrophil infiltration and phagocytic activity in CCR2 2/2 mice at 24 hours. However, impaired phagocytic activity was observed at 48 hours compared with the WT. Production of CCL-2 and macrophage chemoattractant protein-5 was increased in the absence of CCR2, thus suggesting a negative feedback mechanism of regulation. Isolated AMs in the CCR2 2/2 mice showed a predominant M1 phenotype compared with the predominant M2 phenotype in WT mice. Taken together, the above results show that CCL-2 is functionally important in the down-modulation of injury and inflammation in LC.Keywords: lung contusion; macrophage chemoattractant protein-1; CC chemokine ligand-2; CC chemokine receptor 2; inflammation Thoracic injury is involved in nearly one-third of all acute trauma admissions (1-4), often including clinically significant lung contusion (LC) with subsequent respiratory deficits. LC is an important independent risk factor for the development of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and ventilator-associated pneumonia in affected patients (1-4), all of which are associated with high mortality and morbidity (5).The clinical pathophysiology of LC includes hypoxemia, hypercarbia, increased work of breathing, and decreased lung volumes and compliance in association with ventilation-perfusion mismatching, intrapulmonary shunting, edema, and segmental lung damage (1, 6, 7). As 30% of patients with LC progress to ALI/ ARDS (1), it is important to delineate the factors responsible for the development of progressive respiratory failure. Several lines of evidence suggest that factors in addition to traumainduced tissue damage may contribute to respiratory failure in LC (1, 3).Macrophage chemoattractant protein (MCP)-1/CC chemokine ligand (CCL)-2 is produced by a number of cells in response to inflammatory stimuli, suc...

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Transcriptional profiling reveals gene expression changes associated with inflammation and cell proliferation following short‐term inhalation exposure to copper oxide nanoparticles

Costa

Gosens

Williams

et al. 2017

J of Applied Toxicology

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Our recent studies revealed a dose-dependent proinflammatory response to copper oxide nanoparticles (CuO NPs) in rats following short-term inhalation exposure for five consecutive days. Here transcriptomics approaches were applied using the same model to assess global gene expression in lung tissues obtained 1 day post-exposure and after a recovery period of 22 days from rats exposed to clean air or 6 hour equivalent doses of 3.3 mg m (low dose) and 13.2 mg m (high dose). Microarray analyses yielded about 1000 differentially expressed genes in the high-dose group and 200 in low-dose compared to the clean air control group, and less than 20 after the recovery period. Pathway analysis indicated cell proliferation/survival and inflammation as the main processes triggered by exposure to CuO NPs. We did not find significant perturbations of pathways related to oxidative stress. Upregulation of epithelial cell transforming protein 2 (Ect2), a known oncogene, was noted and ECT2 protein was upregulated in the lungs of exposed animals. Proliferation of alveolar epithelial cells was demonstrated based on Ki67 expression. The gene encoding monocyte chemoattractant protein 1 (or CCL2) was also upregulated and this was confirmed by immunohistochemistry. However, no aberrant DNA methylation of inflammation-associated genes was observed. In conclusion, we have found that inhalation of CuO NPs in rats causes upregulation of the oncoprotein ECT2 and the chemokine CCL2 and other proinflammatory markers as well as proliferation in bronchoalveolar epithelium after a short-term inhalation exposure. Thus, pathways known to be associated with neoplastic processes and inflammation were affected in this model.

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Monocyte Chemoattractant Protein–1 Released from Alveolar Macrophages Mediates the Systemic Inflammation of Acute Alveolar Hypoxia

Cited by 52 publications

References 48 publications

Renin released from mast cells activated by circulating MCP-1 initiates the microvascular phase of the systemic inflammation of alveolar hypoxia

Renin released from mast cells activated by circulating MCP-1 initiates the microvascular phase of the systemic inflammation of alveolar hypoxia

Role of Macrophage Chemoattractant Protein-1 in Acute Inflammation after Lung Contusion

Transcriptional profiling reveals gene expression changes associated with inflammation and cell proliferation following short‐term inhalation exposure to copper oxide nanoparticles

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