Limits...
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

Pulmonary macrophages in IH rats expressed pro-inflammatory markers including iNOS.The pulmonary macrophages were obtained from BALF after 6 weeks of IH or normoxic exposure. (A) Immunocytochemical staining of pro-inflammatory markers iNOS, CD11c, and IL-6 was performed. (B) Western blot analysis of iNOS, IL-6, and TNFα in BALF-derived macrophages (n = 5 each, mean ± S.D.). *Significant difference between the N and IH rats (*P<0.05).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4489089&req=5

pone.0131923.g002: Pulmonary macrophages in IH rats expressed pro-inflammatory markers including iNOS.The pulmonary macrophages were obtained from BALF after 6 weeks of IH or normoxic exposure. (A) Immunocytochemical staining of pro-inflammatory markers iNOS, CD11c, and IL-6 was performed. (B) Western blot analysis of iNOS, IL-6, and TNFα in BALF-derived macrophages (n = 5 each, mean ± S.D.). *Significant difference between the N and IH rats (*P<0.05).

Mentions: To characterize the phenotype of pulmonary macrophages in the lungs of IH, immunocytochemical staining and western blotting were performed using iNOS, CD11c, and IL-6. LPS administered rats were used for a positive control of inflammatory macrophages (S6 Fig). Pro-inflammatory markers such as iNOS, CD11c, and IL-6 were detected in IH rat macrophages, but not those of N rats (Fig 2A). Western blotting demonstrated that the protein expression levels of pro-inflammatory markers; i.e., iNOS, IL-6, and TNFα were significantly upregulated in IH-induced macrophages (Fig 2B). These results indicated that the IH stimulation promoted differentiation of the pulmonary macrophages into a pro-inflammatory type.


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)

Pulmonary macrophages in IH rats expressed pro-inflammatory markers including iNOS.The pulmonary macrophages were obtained from BALF after 6 weeks of IH or normoxic exposure. (A) Immunocytochemical staining of pro-inflammatory markers iNOS, CD11c, and IL-6 was performed. (B) Western blot analysis of iNOS, IL-6, and TNFα in BALF-derived macrophages (n = 5 each, mean ± S.D.). *Significant difference between the N and IH rats (*P<0.05).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0131923.g002: Pulmonary macrophages in IH rats expressed pro-inflammatory markers including iNOS.The pulmonary macrophages were obtained from BALF after 6 weeks of IH or normoxic exposure. (A) Immunocytochemical staining of pro-inflammatory markers iNOS, CD11c, and IL-6 was performed. (B) Western blot analysis of iNOS, IL-6, and TNFα in BALF-derived macrophages (n = 5 each, mean ± S.D.). *Significant difference between the N and IH rats (*P<0.05).
Mentions: To characterize the phenotype of pulmonary macrophages in the lungs of IH, immunocytochemical staining and western blotting were performed using iNOS, CD11c, and IL-6. LPS administered rats were used for a positive control of inflammatory macrophages (S6 Fig). Pro-inflammatory markers such as iNOS, CD11c, and IL-6 were detected in IH rat macrophages, but not those of N rats (Fig 2A). Western blotting demonstrated that the protein expression levels of pro-inflammatory markers; i.e., iNOS, IL-6, and TNFα were significantly upregulated in IH-induced macrophages (Fig 2B). These results indicated that the IH stimulation promoted differentiation of the pulmonary macrophages into a pro-inflammatory type.

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