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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

Blockade of iNOS completely restores attenuated HPV in IH rats.(A) Representative images of the branching pattern of the small pulmonary arteries at the baseline and after the administration of L-NIL (selective iNOS inhibitor). The black arrows point to constricted pulmonary arteries. (B, C) Relationship between vessel size and the extent of the pulmonary vasoconstriction induced in response to acute hypoxia with or without selective L-NIL treatment. Data are presented as mean ± S.E.M. values. *Significant change in vessel diameter compared with the baseline conditions (**P<0.01). †Significant difference between the N and IH rats (†P<0.05; ††P<0.01). ‡Significant difference compared with the no drug conditions (‡P<0.05, ‡‡P<0.01).
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pone.0131923.g005: Blockade of iNOS completely restores attenuated HPV in IH rats.(A) Representative images of the branching pattern of the small pulmonary arteries at the baseline and after the administration of L-NIL (selective iNOS inhibitor). The black arrows point to constricted pulmonary arteries. (B, C) Relationship between vessel size and the extent of the pulmonary vasoconstriction induced in response to acute hypoxia with or without selective L-NIL treatment. Data are presented as mean ± S.E.M. values. *Significant change in vessel diameter compared with the baseline conditions (**P<0.01). †Significant difference between the N and IH rats (†P<0.05; ††P<0.01). ‡Significant difference compared with the no drug conditions (‡P<0.05, ‡‡P<0.01).

Mentions: In IH rats, SR59230A, a lipophilic selective β3-blocker, restored the attenuated HPV to almost the same level as was seen in N rats (Fig 4A and 4C). In contrast, SR59230A had no significant effect on the HPV seen in N rats. Pretreatment with the selective iNOS inhibitor L-NIL also restored the attenuated HPV in the same manner as SR59230A (Fig 5). These results suggest that IH activates both a β3AR-mediated and iNOS-mediated vasodilatory mechanism to attenuate 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)

Blockade of iNOS completely restores attenuated HPV in IH rats.(A) Representative images of the branching pattern of the small pulmonary arteries at the baseline and after the administration of L-NIL (selective iNOS inhibitor). The black arrows point to constricted pulmonary arteries. (B, C) Relationship between vessel size and the extent of the pulmonary vasoconstriction induced in response to acute hypoxia with or without selective L-NIL treatment. Data are presented as mean ± S.E.M. values. *Significant change in vessel diameter compared with the baseline conditions (**P<0.01). †Significant difference between the N and IH rats (†P<0.05; ††P<0.01). ‡Significant difference compared with the no drug conditions (‡P<0.05, ‡‡P<0.01).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0131923.g005: Blockade of iNOS completely restores attenuated HPV in IH rats.(A) Representative images of the branching pattern of the small pulmonary arteries at the baseline and after the administration of L-NIL (selective iNOS inhibitor). The black arrows point to constricted pulmonary arteries. (B, C) Relationship between vessel size and the extent of the pulmonary vasoconstriction induced in response to acute hypoxia with or without selective L-NIL treatment. Data are presented as mean ± S.E.M. values. *Significant change in vessel diameter compared with the baseline conditions (**P<0.01). †Significant difference between the N and IH rats (†P<0.05; ††P<0.01). ‡Significant difference compared with the no drug conditions (‡P<0.05, ‡‡P<0.01).
Mentions: In IH rats, SR59230A, a lipophilic selective β3-blocker, restored the attenuated HPV to almost the same level as was seen in N rats (Fig 4A and 4C). In contrast, SR59230A had no significant effect on the HPV seen in N rats. Pretreatment with the selective iNOS inhibitor L-NIL also restored the attenuated HPV in the same manner as SR59230A (Fig 5). These results suggest that IH activates both a β3AR-mediated and iNOS-mediated vasodilatory mechanism to attenuate 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