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Pulmonary Macrophages Attenuate Hypoxic Pulmonary Vasoconstriction via β3AR/iNOS Pathway in Rats Exposed to Chronic Intermittent Hypoxia.

Nagai H, Kuwahira I, Schwenke DO, Tsuchimochi H, Nara A, Ogura S, Sonobe T, Inagaki T, Fujii Y, Yamaguchi R, Wingenfeld L, Umetani K, Shimosawa T, Yoshida K, Uemura K, Pearson JT, Shirai M - PLoS ONE (2015)

Bottom Line: Interestingly, chronic IH induced the migration of circulating monocytes into the lungs and the predominant increase in the number of pro-inflammatory pulmonary macrophages.In these macrophages, both β3AR and iNOS were upregulated and stimulation of the β3AR/iNOS pathway in vitro caused them to promote NO secretion.These results suggest that circulating monocyte-derived pulmonary macrophages attenuate HPV via activation of β3AR/iNOS signaling in chronic IH.

View Article: PubMed Central - PubMed

Affiliation: Department of Forensic Medicine, Tokyo Medical and Dental University, Tokyo, Japan; Department of Forensic Medicine, The University of Tokyo, Tokyo, Japan; Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan.

ABSTRACT
Chronic intermittent hypoxia (IH) induces activation of the sympathoadrenal system, which plays a pivotal role in attenuating hypoxic pulmonary vasoconstriction (HPV) via central β1-adrenergic receptors (AR) (brain) and peripheral β2AR (pulmonary arteries). Prolonged hypercatecholemia has been shown to upregulate β3AR. However, the relationship between IH and β3AR in the modification of HPV is unknown. It has been observed that chronic stimulation of β3AR upregulates inducible nitric oxide synthase (iNOS) in cardiomyocytes and that IH exposure causes expression of iNOS in RAW264.7 macrophages. iNOS has been shown to have the ability to dilate pulmonary vessels. Hence, we hypothesized that chronic IH activates β3AR/iNOS signaling in pulmonary macrophages, leading to the promotion of NO secretion and attenuated HPV. Sprague-Dawley rats were exposed to IH (3-min periods of 4-21% O2) for 8 h/d for 6 weeks. The urinary catecholamine concentrations of IH rats were high compared with those of controls, indicating activation of the sympathoadrenal system following chronic IH. Interestingly, chronic IH induced the migration of circulating monocytes into the lungs and the predominant increase in the number of pro-inflammatory pulmonary macrophages. In these macrophages, both β3AR and iNOS were upregulated and stimulation of the β3AR/iNOS pathway in vitro caused them to promote NO secretion. Furthermore, in vivo synchrotron radiation microangiography showed that HPV was significantly attenuated in IH rats and the attenuated HPV was fully restored by blockade of β3AR/iNOS pathway or depletion of pulmonary macrophages. These results suggest that circulating monocyte-derived pulmonary macrophages attenuate HPV via activation of β3AR/iNOS signaling in chronic IH.

No MeSH data available.


Related in: MedlinePlus

Stimulation of β3AR dilates pulmonary arteries via iNOS-dependent signaling in IH rats.(A) Representative microangiographic images showing the branching pattern of the small pulmonary arteries at the baseline and after the administration of each drug. The white arrows point to branches of dilated pulmonary arteries or small pulmonary arteries that were first detected after the administration of CL316243 (a selective β3-agonist). The tungsten wire in the lower right corner of each image is a reference wire that measures 50 μm in diameter. (B) Extent of the change in vessel diameter induced in response to the administration of CL316243 with pretreatment of hexamethonium bromide (C6) in the N and IH rats. Data are presented as mean ± S.E.M. values. *Significant change in vessel diameter compared with the baseline conditions (*P<0.05; **P<0.01). †Significant difference between the N and IH rats (†P<0.05; ††P<0.01). (C, D) Percentage change in the mean diameter of small pulmonary arteries in response to the administration of CL316243 after pretreatment of with either L-NAME or L-NIL. Data are presented as mean ± S.E.M. values.
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pone.0131923.g006: Stimulation of β3AR dilates pulmonary arteries via iNOS-dependent signaling in IH rats.(A) Representative microangiographic images showing the branching pattern of the small pulmonary arteries at the baseline and after the administration of each drug. The white arrows point to branches of dilated pulmonary arteries or small pulmonary arteries that were first detected after the administration of CL316243 (a selective β3-agonist). The tungsten wire in the lower right corner of each image is a reference wire that measures 50 μm in diameter. (B) Extent of the change in vessel diameter induced in response to the administration of CL316243 with pretreatment of hexamethonium bromide (C6) in the N and IH rats. Data are presented as mean ± S.E.M. values. *Significant change in vessel diameter compared with the baseline conditions (*P<0.05; **P<0.01). †Significant difference between the N and IH rats (†P<0.05; ††P<0.01). (C, D) Percentage change in the mean diameter of small pulmonary arteries in response to the administration of CL316243 after pretreatment of with either L-NAME or L-NIL. Data are presented as mean ± S.E.M. values.

Mentions: To assess whether peripheral β3AR, but not the β3AR in the central nervous system, contribute to HPV attenuation in IH, CL316243 was administered under ganglionic blockade with hexamethonium bromide. In IH rats, CL316243 induced extensive dilatation of the small pulmonary arteries, particularly in the arteries with ID of 100–500 μm (Fig 6A and 6B). In contrast, CL316243 had no significant effect in N rats. These results indicate that peripheral β3AR were activated to a much greater extent in IH rats than in N rats, and strongly suggest that peripheral β3AR contributed to the HPV attenuation observed in IH rats.


Pulmonary Macrophages Attenuate Hypoxic Pulmonary Vasoconstriction via β3AR/iNOS Pathway in Rats Exposed to Chronic Intermittent Hypoxia.

Nagai H, Kuwahira I, Schwenke DO, Tsuchimochi H, Nara A, Ogura S, Sonobe T, Inagaki T, Fujii Y, Yamaguchi R, Wingenfeld L, Umetani K, Shimosawa T, Yoshida K, Uemura K, Pearson JT, Shirai M - PLoS ONE (2015)

Stimulation of β3AR dilates pulmonary arteries via iNOS-dependent signaling in IH rats.(A) Representative microangiographic images showing the branching pattern of the small pulmonary arteries at the baseline and after the administration of each drug. The white arrows point to branches of dilated pulmonary arteries or small pulmonary arteries that were first detected after the administration of CL316243 (a selective β3-agonist). The tungsten wire in the lower right corner of each image is a reference wire that measures 50 μm in diameter. (B) Extent of the change in vessel diameter induced in response to the administration of CL316243 with pretreatment of hexamethonium bromide (C6) in the N and IH rats. Data are presented as mean ± S.E.M. values. *Significant change in vessel diameter compared with the baseline conditions (*P<0.05; **P<0.01). †Significant difference between the N and IH rats (†P<0.05; ††P<0.01). (C, D) Percentage change in the mean diameter of small pulmonary arteries in response to the administration of CL316243 after pretreatment of with either L-NAME or L-NIL. Data are presented as mean ± S.E.M. values.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4489089&req=5

pone.0131923.g006: Stimulation of β3AR dilates pulmonary arteries via iNOS-dependent signaling in IH rats.(A) Representative microangiographic images showing the branching pattern of the small pulmonary arteries at the baseline and after the administration of each drug. The white arrows point to branches of dilated pulmonary arteries or small pulmonary arteries that were first detected after the administration of CL316243 (a selective β3-agonist). The tungsten wire in the lower right corner of each image is a reference wire that measures 50 μm in diameter. (B) Extent of the change in vessel diameter induced in response to the administration of CL316243 with pretreatment of hexamethonium bromide (C6) in the N and IH rats. Data are presented as mean ± S.E.M. values. *Significant change in vessel diameter compared with the baseline conditions (*P<0.05; **P<0.01). †Significant difference between the N and IH rats (†P<0.05; ††P<0.01). (C, D) Percentage change in the mean diameter of small pulmonary arteries in response to the administration of CL316243 after pretreatment of with either L-NAME or L-NIL. Data are presented as mean ± S.E.M. values.
Mentions: To assess whether peripheral β3AR, but not the β3AR in the central nervous system, contribute to HPV attenuation in IH, CL316243 was administered under ganglionic blockade with hexamethonium bromide. In IH rats, CL316243 induced extensive dilatation of the small pulmonary arteries, particularly in the arteries with ID of 100–500 μm (Fig 6A and 6B). In contrast, CL316243 had no significant effect in N rats. These results indicate that peripheral β3AR were activated to a much greater extent in IH rats than in N rats, and strongly suggest that peripheral β3AR contributed to the HPV attenuation observed in IH rats.

Bottom Line: Interestingly, chronic IH induced the migration of circulating monocytes into the lungs and the predominant increase in the number of pro-inflammatory pulmonary macrophages.In these macrophages, both β3AR and iNOS were upregulated and stimulation of the β3AR/iNOS pathway in vitro caused them to promote NO secretion.These results suggest that circulating monocyte-derived pulmonary macrophages attenuate HPV via activation of β3AR/iNOS signaling in chronic IH.

View Article: PubMed Central - PubMed

Affiliation: Department of Forensic Medicine, Tokyo Medical and Dental University, Tokyo, Japan; Department of Forensic Medicine, The University of Tokyo, Tokyo, Japan; Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan.

ABSTRACT
Chronic intermittent hypoxia (IH) induces activation of the sympathoadrenal system, which plays a pivotal role in attenuating hypoxic pulmonary vasoconstriction (HPV) via central β1-adrenergic receptors (AR) (brain) and peripheral β2AR (pulmonary arteries). Prolonged hypercatecholemia has been shown to upregulate β3AR. However, the relationship between IH and β3AR in the modification of HPV is unknown. It has been observed that chronic stimulation of β3AR upregulates inducible nitric oxide synthase (iNOS) in cardiomyocytes and that IH exposure causes expression of iNOS in RAW264.7 macrophages. iNOS has been shown to have the ability to dilate pulmonary vessels. Hence, we hypothesized that chronic IH activates β3AR/iNOS signaling in pulmonary macrophages, leading to the promotion of NO secretion and attenuated HPV. Sprague-Dawley rats were exposed to IH (3-min periods of 4-21% O2) for 8 h/d for 6 weeks. The urinary catecholamine concentrations of IH rats were high compared with those of controls, indicating activation of the sympathoadrenal system following chronic IH. Interestingly, chronic IH induced the migration of circulating monocytes into the lungs and the predominant increase in the number of pro-inflammatory pulmonary macrophages. In these macrophages, both β3AR and iNOS were upregulated and stimulation of the β3AR/iNOS pathway in vitro caused them to promote NO secretion. Furthermore, in vivo synchrotron radiation microangiography showed that HPV was significantly attenuated in IH rats and the attenuated HPV was fully restored by blockade of β3AR/iNOS pathway or depletion of pulmonary macrophages. These results suggest that circulating monocyte-derived pulmonary macrophages attenuate HPV via activation of β3AR/iNOS signaling in chronic IH.

No MeSH data available.


Related in: MedlinePlus