Plasma from conscious hypoxic rats stimulates leukocyte-endothelial interactions in normoxic cremaster venules

Orth, Teresa; Allen, Julie; Wood, John G.; González, Norberto C.

doi:10.1152/japplphysiol.00932.2004

Cited by 13 publications

(36 citation statements)

References 21 publications

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“…Conversely, an MCP-1 receptor antagonist blocks alveolar hypoxia-induced systemic inflammation in intact rats. This is consistent with previous observations that AMO depletion prevents alveolar hypoxia-induced systemic inflammation, and that plasma from intact hypoxic rats, but not of AMO-depleted rats, elicits inflammation in normoxic tissues [28,88]. …”

Section: Amos Are Required For Systemic Inflammation Under Alveolar Hsupporting

confidence: 93%

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 Hsupporting

confidence: 93%

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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“…Our previous work provided compelling evidence that the systemic inflammation of hypoxia is not initiated by reduced tissue PO 2 , but rather by a mediator released from AMØ and transported by the circulation (7,8,12,13,16,19). A role for AMØ-borne MCP-1 as the putative mediator was suggested by the recent finding that primary cultures of AMØ, but not of peritoneal MCs or peritoneal macrophages, release MCP-1 within 30 minutes of exposure to hypoxia (16).…”

Section: Discussionmentioning

confidence: 97%

“…The effect of hypoxic rat plasma is not attributable to inflammatory mediators released into plasma by activated MCs or adherent leukocytes of the donor rat. Furthermore, the agents responsible for inflammation are not generated by blood cells (19). (4) A topical application of supernatant from hypoxic AMØ produces the degranulation of MCs, increased leukocyte-endothelial adherence, and increased vascular permeability in the normoxic cremaster (12).…”

mentioning

confidence: 99%

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

Chao¹,

Donham²,

Rooijen³

et al. 2011

Am J Respir Cell Mol Biol

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Alveolar hypoxia produces rapid systemic inflammation in rats. Several lines of evidence suggest that the inflammation is not initiated by low systemic tissue partial pressure of oxygen (PO 2 ) but by a mediator released into the circulation by hypoxic alveolar macrophages. The mediator activates tissue mast cells to initiate inflammation. Monocyte chemoattractant protein-1/Chemokine (C-C motif) ligand 2 (MCP-1/CCL2) is rapidly released by hypoxic alveolar macrophages. This study investigated whether MCP-1 is the mediator of the systemic inflammation of alveolar hypoxia. Experiments in rats and in alveolar macrophages and peritoneal mast cells led to several results. (1) Alveolar hypoxia (10% O 2 breathing, 60 minutes) produced a rapid (5-minute) increase in plasma MCP-1 concentrations in conscious intact rats but not in alveolar macrophage-depleted rats. (2) Degranulation occurred when mast cells were immersed in the plasma of hypoxic intact rats but not in the plasma of alveolar macrophage-depleted rats. (3) MCP-1 added to normoxic rat plasma and the supernatant of normoxic alveolar macrophages produced a concentration-dependent degranulation of immersed mast cells. (4) MCP-1 applied to the mesentery of normoxic intact rats replicated the inflammation of alveolar hypoxia. (5) The CCR2b receptor antagonist RS-102895 prevented the mesenteric inflammation of alveolar hypoxia in intact rats. Additional data suggest that a cofactor constitutively generated in alveolar macrophages and present in normoxic body fluids is necessary for MCP-1 to activate mast cells at biologically relevant concentrations. We conclude that alveolar macrophage-borne MCP-1 is a key agent in the initiation of the systemic inflammation of alveolar hypoxia.Keywords: alveolar macrophages; alveolar hypoxia; systemic inflammation; monocyte chemoattractant protein-1; mast cells Alveolar hypoxia occurs in a number of clinical settings, and is frequently associated with systemic effects, some of which are thought to include an inflammatory component (1-5). The reduction of inspired partial pressure of oxygen (PO 2 ) in rats induces a rapid and widespread inflammatory response in the mesentery (6), skeletal muscle (7,8), and brain (9), as characterized by increased microvascular concentrations of reactive O 2 species (10), increased leukocyte endothelial adhesive interactions (6), leukocyte emigration (11), increased vascular permeability as evidenced by the extravasation of albumin in the presence of reduced blood flow (11-13), and the degranulation of perivascular mast cells (MCs) (7,8,14). The degranulation of MCs is a key event: the MC stabilizer cromolyn attenuates all of the markers of inflammation induced by alveolar hypoxia (14). MCs are abundant in the microcirculatory beds in which the inflammatory effects of hypoxia were demonstrated (15-17), and are known to degranulate and release various inflammatory mediators, including leukotriene B 4 and platelet activating factor, which were shown to participate in the systemic inflammation of hypo...

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“…This idea is supported by two lines of evidence: first, selective reduction of cremaster PO 2 does not produce mast cell degranulation and inflammation in the cremaster microcirculation unless alveolar PO 2 is also reduced (2, 3); second, plasma obtained from hypoxic rats applied to the normoxic cremaster produces an inflammatory response similar to that elicited by alveolar hypoxia (8). The response to hypoxic rat plasma is not due to inflammatory mediators released into plasma by activated mast cells or adherent leukocytes of the donor rat; furthermore, the agent(s) responsible for the inflammation is not generated by blood cells (8). Further investigation has shown that the putative mediator activates mast cells and initiates an inflammatory cascade that includes activation of the renin-angiotensin (Ang) system (RAS) (9).…”

mentioning

confidence: 94%

The Systemic Inflammation of Alveolar Hypoxia Is Initiated by Alveolar Macrophage–Borne Mediator(s)

Chao

Wood²,

Blanco³

et al. 2009

Am J Respir Cell Mol Biol

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Alveolar hypoxia produces widespread systemic inflammation in rats. The inflammation appears to be triggered by activation of mast cells by a mediator released from alveolar macrophages, not by the reduced systemic partial pressure of oxygen (PO 2 ). If this is correct, the following should apply: (1) neither mast cells nor tissue macrophages should be directly activated by hypoxia; and (2) mast cells should be activated when in contact with hypoxic alveolar macrophages, but not with hypoxic tissue macrophages. We sought here to determine whether hypoxia activates isolated alveolar macrophages, peritoneal macrophages, and peritoneal mast cells, and to study the response of the microcirculation to supernatants of these cultures. Rat mesenteric microcirculation intravital microscopy was combined with primary cultures of alveolar macrophages, peritoneal macrophages, and peritoneal mast cells. Supernatant of hypoxic alveolar macrophages, but not of hypoxic peritoneal macrophages, produced inflammation in mesentery. Hypoxia induced a respiratory burst in alveolar, but not peritoneal macrophages. Cultured peritoneal mast cells did not degranulate with hypoxia. Immersion of mast cells in supernatant of hypoxic alveolar macrophages, but not in supernatant of hypoxic peritoneal macrophages, induced mast cell degranulation. Hypoxia induced release of monocyte chemoattractant protein-1, a mast cell secretagogue, from alveolar, but not peritoneal macrophages or mast cells. We conclude that a mediator released by hypoxic alveolar macrophages activates mast cells and triggers systemic inflammation. Reduced systemic PO 2 and activation of tissue macrophages do not play a role in this phenomenon. The inflammation could contribute to systemic effects of diseases featuring alveolar hypoxia.Keywords: hypoxia; systemic inflammation; alveolar macrophages; mast cells; monocyte chemoattractant protein Alveolar hypoxia, induced by reduction of inspired PO 2 , initiates a rapid and widespread inflammatory response in mesentery (1), skeletal muscle (2, 3), and brain (4) of rats. The inflammation is characterized by increased microvascular levels of reactive oxygen species (ROS) (5), perivascular mast cell degranulation (2, 3, 6), increased leukocyte-endothelial adhesive interactions (1), and extravasation of albumin (7).Studies in the cremaster microcirculation suggest that the inflammation elicited by alveolar hypoxia is not triggered by the reduction of cremaster PO 2 , but rather by a mediator released from a distant site and transported by the circulation. This idea is supported by two lines of evidence: first, selective reduction of cremaster PO 2 does not produce mast cell degranulation and inflammation in the cremaster microcirculation unless alveolar PO 2 is also reduced (2, 3); second, plasma obtained from hypoxic rats applied to the normoxic cremaster produces an inflammatory response similar to that elicited by alveolar hypoxia (8). The response to hypoxic rat plasma is not due to inflammatory mediators released into plasma by...

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Plasma from conscious hypoxic rats stimulates leukocyte-endothelial interactions in normoxic cremaster venules

Cited by 13 publications

References 21 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

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

The Systemic Inflammation of Alveolar Hypoxia Is Initiated by Alveolar Macrophage–Borne Mediator(s)

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