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

Chao, Jie; Blanco, Gustavo; Wood, John G.; González, Norberto C.

doi:10.1152/ajpheart.00461.2011

Cited by 23 publications

(23 citation statements)

References 29 publications

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“…Studies by Chao et al [26,27,28,86] confirm that alveolar hypoxia-induced systemic inflammation requires AMO activation, independent of reduced systemic PO 2 levels or the activation of tissue macrophages. Another study found that plasma from alveolar hypoxic rats evokes an inflammatory response in tissues of normoxic rats, which suggests that a mediator released by hypoxic AMOs activates mast cells and triggers systemic inflammation [87].…”

Section: Amos Are Required For Systemic Inflammation Under Alveolar Hmentioning

confidence: 96%

“…It has been reported that MCP-1-induced MC degranulation is involved in RAS activation under alveolar hypoxia [86]. Western blots and immunocytochemistry demonstrated the presence of renin and angiotensin-converting enzyme in mast cells and their release upon degranulation.…”

Section: Activated Systemic Inflammation Is Critical For the Progressmentioning

confidence: 98%

“…An activated RAS mediates microvascular inflammation by increasing leukocyte-endothelial interactions and vascular hyperpermeability [86,97]. It has been reported that MCP-1-induced MC degranulation is involved in RAS activation under alveolar hypoxia [86].…”

Section: Activated Systemic Inflammation Is Critical For the Progressmentioning

confidence: 99%

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Alveolar Hypoxia-Induced Pulmonary Inflammation: From Local Initiation to Secondary Promotion by Activated Systemic Inflammation

Chen¹,

Yang²,

Li³

et al. 2016

J Vasc Res

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Pulmonary hypertension (PH) is a pathological condition with high mortality and morbidity. Hypoxic PH (HPH) is a common form of PH occurring mainly due to lung disease and/or hypoxia. Most causes of HPH are associated with persistent or intermittent alveolar hypoxia, including exposure to high altitude and chronic obstructive respiratory disease. Recent evidence suggests that inflammation is a critical step for HPH initiation and development. A detailed understanding of the initiation and progression of pulmonary inflammation would help in exploring potential clinical treatments for HPH. In this review, the mechanism for alveolar hypoxia-induced local lung inflammation and its progression are discussed as follows: (1) low alveolar PO₂ levels activate resident lung cells, mainly the alveolar macrophages, which initiate pulmonary inflammation; (2) systemic inflammation is induced by alveolar hypoxia through alveolar macrophage activation; (3) monocytes are recruited into the pulmonary circulation by alveolar hypoxia-induced macrophage activation, which then contributes to the progression of pulmonary inflammation during the chronic phase of alveolar hypoxia, and (4) alveolar hypoxia-induced systemic inflammation contributes to the development of HPH. We hypothesize that a combination of alveolar hypoxia-induced local lung inflammation and the initiation of systemic inflammation (“second hit”) is essential for HPH progression.

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Section: Amos Are Required For Systemic Inflammation Under Alveolar Hmentioning

confidence: 96%

Section: Activated Systemic Inflammation Is Critical For the Progressmentioning

confidence: 98%

See 1 more Smart Citation

Alveolar Hypoxia-Induced Pulmonary Inflammation: From Local Initiation to Secondary Promotion by Activated Systemic Inflammation

Chen¹,

Yang²,

Li³

et al. 2016

J Vasc Res

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“…Captopril at the concentration of 1 mM completely blocks ANG II generation induced by MCP-1 in rat mast cells (4). Enalapril at 150 M completely inhibits tissue factor upregulation in coculture of human monocytic cells and human coronary artery endothelial cells (23).…”

Section: Renin Ace Cathepsin G and At 1 Receptor Inhibitionmentioning

confidence: 99%

Role of renin-angiotensin system in activation of macrophages by modified lipoproteins

Rafatian

Milne

Leenen

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Rafatian N, Milne RW, Leenen FH, Whitman SC. Role of reninangiotensin system in activation of macrophages by modified lipoproteins. Am J Physiol Heart Circ Physiol 305: H1309-H1320, 2013. First published August 30, 2013; doi:10.1152/ajpheart.00826.2012.-Angiotensin II favors the development of atherosclerosis. Our goal was to determine if foam cell formation increases angiotensin II generation by the endogenous renin-angiotensin system (RAS) and if endogenously produced angiotensin II promotes lipid accumulation in macrophages. Differentiated THP-1 cells were treated with acetylated low-density lipoproteins (ac-LDL), native LDL (n-LDL), or no LDL. Expression of RAS genes was assessed and angiotensin I/II levels were quantified in media and cell lysate. Ac-LDL increased angiotensin I/II levels and the angiotensin II/I ratio in cells and media after foam cell formation. Renin mRNA or activity did not change, but renin blockade completely inhibited the increase in angiotensin II. Angiotensinogen mRNA but not protein level was increased. Angiotensin-converting enzyme (ACE) and cathepsin G mRNA and activities were enhanced by ac-LDL. Inhibition of renin, ACE, or the angiotensin II receptor 1 (AT 1-receptor) largely abolished cholesteryl ester formation in cells exposed to ac-LDL and decreased scavenger receptor A (SR-A) and acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT-1) protein levels. Inhibition of renin or the AT 1-receptor in cells treated with oxidized LDL also decreased SR-A and ACAT-1 protein and foam cell formation. ac-LDL also increased angiotensin II by human peripheral blood monocyte-derived macrophages, whereas blockade of renin decreased cholesterol ester formation in these macrophages. These findings indicate that, during foam cell formation, angiotensin II generation by the endogenous RAS is stimulated and that endogenously generated angiotensin II is crucial for cholesterol ester accumulation in macrophages exposed to modified LDL. (6,33,34). All components of the renin-angiotensin system (RAS) are present in atherosclerotic lesions (6). ANG II in atherosclerotic lesions localizes in macrophages (28). Human macrophages express all components of the RAS and release ANG II (25). Macrophages also express other enzymes that are able to produce ANG II such as cathepsin G, which can generate ANG II from either angiotensin I (ANG I) or angiotensinogen (29). Low-density lipoprotein (LDL) receptor-deficient atherosclerotic mice with renin deficiency in their bone marrow have reduced atherosclerotic lesion size, suggesting the importance of macrophage-derived ANG II in atherosclerosis (5).Lipid-laden macrophages are the predominant cell type in early stages of atherosclerosis (5) Although the expression of the RAS genes and ANG II release have been shown in macrophages (25), changes in the expression of these genes and their effects on the final product of the system (ANG II) have not yet been studied in foam cells. The role of locally generated ANG II in foam cell formation independently of circulating...

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“…The possible role of an AMO-borne circulating mediator as the trigger of inflammation in systemic microvascular beds was suggested by the observation that the inflammation occurs only when alveolar PO 2 is reduced, independent of the systemic microvascular PO 2 (6,32), and that topical application of plasma from hypoxic rats and of supernatant of hypoxic AMO induces inflammation in tissues of normoxic animals (6,11,26). The AMO-borne mediator, which has been identified as monocyte chemoattractant protein-1 (MCP-1), a chemokine of the CC family, also known as CCL2, is transported by the circulation and activates MCs (3), which release renin and activate the local renin-angiotensin system (RAS) system (5). Angiotensin II (ANG II) generated as a result of the RAS activation initiates the microvascular phase of the inflammatory response (4,5,12).…”

mentioning

confidence: 99%

Dexamethasone blocks the systemic inflammation of alveolar hypoxia at several sites in the inflammatory cascade

Chao

Viets

Donham

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Alveolar hypoxia produces a rapid and widespread systemic inflammation in rats. The inflammation is initiated by the release into the circulation of monocyte chemoattractant protein-1 (MCP-1) from alveolar macrophages (AMO) activated by the low alveolar Po(2). Circulating MCP-1 induces mast cell (MC) degranulation with renin release and activation of the local renin-angiotensin system, leading to microvascular leukocyte recruitment and increased vascular permeability. We investigated the effect of dexamethasone, a synthetic anti-inflammatory glucocorticoid, on the development of the systemic inflammation of alveolar hypoxia and its site(s) of action in the inflammatory cascade. The inflammatory steps investigated were the activation of primary cultures of AMO by hypoxia, the degranulation of MCs by MCP-1 in the mesentery microcirculation of rats, and the effect of angiotensin II (ANG II) on the leukocyte/endothelial interface of the mesentery microcirculation. Dexamethasone prevented the mesentery inflammation in conscious rats breathing 10% O(2) for 4 h by acting in all key steps of the inflammatory cascade. Dexamethasone: 1) blocked the hypoxia-induced AMO activation and the release of MCP-1 and abolished the increase in plasma MCP-1 of conscious, hypoxic rats; 2) prevented the MCP-1-induced degranulation of mesentery perivascular MCs and reduced the number of peritoneal MCs, and 3) blocked the leukocyte-endothelial adherence and the extravasation of albumin induced by topical ANG II in the mesentery. The effect at each site was sufficient to prevent the AMO-initiated inflammation of hypoxia. These results may explain the effectiveness of dexamethasone in the treatment of the systemic effects of alveolar hypoxia.

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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

Cited by 23 publications

References 29 publications

Alveolar Hypoxia-Induced Pulmonary Inflammation: From Local Initiation to Secondary Promotion by Activated Systemic Inflammation

Alveolar Hypoxia-Induced Pulmonary Inflammation: From Local Initiation to Secondary Promotion by Activated Systemic Inflammation

Role of renin-angiotensin system in activation of macrophages by modified lipoproteins

Dexamethasone blocks the systemic inflammation of alveolar hypoxia at several sites in the inflammatory cascade

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