The protective role of localized nitric oxide production during inflammation may be mediated by the heme oxygenase-1/carbon monoxide pathway

Masahiro Iwata; Takayuki Inoue; Yuji Asai; Kiyomi Hori; Mitsuhiro Fujiwara; Shingo Matsuo; Wakako Tsuchida; Shigeyuki Suzuki

doi:10.1016/j.bbrep.2020.100790

The protective role of localized nitric oxide production during inflammation may be mediated by the heme oxygenase-1/carbon monoxide pathway

Biochem Biophys Rep. 2020 Jul 24:23:100790. doi: 10.1016/j.bbrep.2020.100790. eCollection 2020 Sep.

Authors

Masahiro Iwata^{1

2}, Takayuki Inoue³, Yuji Asai¹, Kiyomi Hori⁴, Mitsuhiro Fujiwara^{2

5}, Shingo Matsuo¹, Wakako Tsuchida⁶, Shigeyuki Suzuki⁷

Affiliations

¹ Department of Rehabilitation, Faculty of Health Sciences, Nihon Fukushi University, 26-2 Higashihaemi-cho, Handa, Aichi, 475-0012, Japan.
² Department of Physical and Occupational Therapy, Nagoya University Graduate School of Medicine, 1-1-20 Daiko-Minami, Higashi-ku, Nagoya, 461-8673, Japan.
³ Department of Rehabilitation, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan.
⁴ Department of Functional Anatomy, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8640, Japan.
⁵ Kamiiida Rehabilitation Hospital, 3-57 Kamiiida Kita-machi, Kita-ku, Nagoya, 462-0802, Japan.
⁶ Department of Life Science and Biotechnology, National Institute of Advanced Industrial Science and Technology (AIST), 2217-14 Hayashi-cho, Takamatsu, Kagawa, 761-0395, Japan.
⁷ Department of Health and Sports Sciences, School of Health Sciences, Asahi University, 1851 Hozumi, Mizuho, Gifu, 501-0296, Japan.

Abstract

Nitric oxide (NO) is an important part of the host defense mechanism; however, it displays both pro- and anti-inflammatory properties depending on its location and concentration. Importantly, excessive or inappropriate NO production can cause tissue damage. Systemic and local administration of NO synthase (NOS) inhibitors ameliorates and may exacerbate the inflammatory response, respectively. Here, we used a carrageenan-induced pleurisy model of acute inflammation in rats to confirm the location-dependent effects of NO and investigate the underlying mechanisms. As expected, localized suppression of NO production exacerbated inflammation, as evidenced by increased pleural exudate volumes and leukocyte counts and enhanced activity of enzymes related to oxidative stress. In contrast, local NO supplementation reduced leukocyte infiltration, vascular permeability, and the activity of oxidative stress-related enzymes. Interestingly, inhibition of heme oxygenase-1 (HO-1) reversed the anti-inflammatory effects of localized NO production, while the addition of hemin (HO-1 substrate) or carbon monoxide (CO; HO-1 metabolite) decreased leukocyte migration and exudation. Together, these findings confirm a protective role for NO at the inflammatory site, which appears to be mediated via NOS induction of the HO-1/CO pathway. Thus, NO supplementation may be a potential new treatment for oxidative stress-associated inflammatory diseases.

Keywords: Acute inflammation; Carbon monoxide; Carrageenan; Heme oxygenase-1; Nitric oxide; Pleurisy.