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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

Acute intratracheal administration of clodronate restores HPV in IH rats.(A) Representative bright-field images and images of immunofluorescent staining using anti-ED-1 antibody of lung sections with or without clodronate. Clodronate (500 μg of clodronate in 100 μL of saline) was injected intratracheally just after the end of the 6-week IH/normoxia exposure period. Calibration bar = 200 μm. (B) Representative microangiographic images of the small pulmonary arteries in the N and IH rats obtained 3 days after the i.t. administration of clodronate. The black arrows point to branches that underwent vasoconstriction. (C) Relationship between vessel size and the extent of the pulmonary vasoconstriction induced in response to acute hypoxia. Data are presented as mean ± S.E.M. values. *Significant change in vessel diameter compared with the baseline conditions (**P<0.01).
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pone.0131923.g007: Acute intratracheal administration of clodronate restores HPV in IH rats.(A) Representative bright-field images and images of immunofluorescent staining using anti-ED-1 antibody of lung sections with or without clodronate. Clodronate (500 μg of clodronate in 100 μL of saline) was injected intratracheally just after the end of the 6-week IH/normoxia exposure period. Calibration bar = 200 μm. (B) Representative microangiographic images of the small pulmonary arteries in the N and IH rats obtained 3 days after the i.t. administration of clodronate. The black arrows point to branches that underwent vasoconstriction. (C) Relationship between vessel size and the extent of the pulmonary vasoconstriction induced in response to acute hypoxia. Data are presented as mean ± S.E.M. values. *Significant change in vessel diameter compared with the baseline conditions (**P<0.01).

Mentions: To investigate whether the macrophages that accumulated in the lungs of the IH rats contributed to the observed HPV attenuation, HPV was evaluated in pulmonary macrophage depleted rats using microangiography. Clodronate was administered into the lungs of IH rats via the trachea immediately after the 6-week IH exposure period. Clodronate strongly suppressed the number of pulmonary macrophages in IH rats to the control level (Fig 7A) and enhanced the attenuated HPV to almost the same level as that seen in N rats (Fig 7B and 7C). These results indicate that the intra-alveolar macrophages that accumulate in the lungs in IH contribute to the attenuation of HPV.


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)

Acute intratracheal administration of clodronate restores HPV in IH rats.(A) Representative bright-field images and images of immunofluorescent staining using anti-ED-1 antibody of lung sections with or without clodronate. Clodronate (500 μg of clodronate in 100 μL of saline) was injected intratracheally just after the end of the 6-week IH/normoxia exposure period. Calibration bar = 200 μm. (B) Representative microangiographic images of the small pulmonary arteries in the N and IH rats obtained 3 days after the i.t. administration of clodronate. The black arrows point to branches that underwent vasoconstriction. (C) Relationship between vessel size and the extent of the pulmonary vasoconstriction induced in response to acute hypoxia. Data are presented as mean ± S.E.M. values. *Significant change in vessel diameter compared with the baseline conditions (**P<0.01).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0131923.g007: Acute intratracheal administration of clodronate restores HPV in IH rats.(A) Representative bright-field images and images of immunofluorescent staining using anti-ED-1 antibody of lung sections with or without clodronate. Clodronate (500 μg of clodronate in 100 μL of saline) was injected intratracheally just after the end of the 6-week IH/normoxia exposure period. Calibration bar = 200 μm. (B) Representative microangiographic images of the small pulmonary arteries in the N and IH rats obtained 3 days after the i.t. administration of clodronate. The black arrows point to branches that underwent vasoconstriction. (C) Relationship between vessel size and the extent of the pulmonary vasoconstriction induced in response to acute hypoxia. Data are presented as mean ± S.E.M. values. *Significant change in vessel diameter compared with the baseline conditions (**P<0.01).
Mentions: To investigate whether the macrophages that accumulated in the lungs of the IH rats contributed to the observed HPV attenuation, HPV was evaluated in pulmonary macrophage depleted rats using microangiography. Clodronate was administered into the lungs of IH rats via the trachea immediately after the 6-week IH exposure period. Clodronate strongly suppressed the number of pulmonary macrophages in IH rats to the control level (Fig 7A) and enhanced the attenuated HPV to almost the same level as that seen in N rats (Fig 7B and 7C). These results indicate that the intra-alveolar macrophages that accumulate in the lungs in IH contribute to the attenuation of HPV.

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