Nitric Oxide as a Surgical Adjuvant

Figures & data

Figure 1.  Nitric oxide is synthesized from l-arginine and molecular oxygen by the NOS group of enzymes.

Inflammatory cytokines (IL-1, TNF-α) upregulated in response to tissue damage induce expression of the inducible NOS gene, leading to a more sustained release of NO. Endothelial NOS and neuronal NOS are constitutively expressed and regulated by calcium fluctuations.

Reprinted with permission from [9] © John Wiley and Sons (2001).

Figure 2.  Macrophage-induced generation of nitric oxide.

Inflammatory cells, primarily macrophages, are responsible for the largest generation of NO in wounds. This corresponds to the early peak of NO in the healing cascade.

Reprinted with permission from [3] © Elsevier (2002).

Figure 3.  Nitric oxide-nanoparticles enhance wound healing in vivo.

(A) Wounds of BALB/c mice at day 7. (B) Wound healing curve. (C) Wound closure percentage of BALB/c mice skin lesions at day 7 relative to the initial 5 mm wound. (D) Histological analysis of untreated, control-np and NO-np treated BALB/c mice at day 7.

np: Nanoparticles.

Reprinted with permission from [16] © American Society for Investigative Pathology (2012).

Figure 4.  In mitochondria, electrons move down the electron transport chain and are transferred to O₂ at complex IV.

When oxygenation is normal, complex I activity is high because a cysteine residue on its ND3 subunit (C-SH) is protected from modification (bottom left). During ischemia, electrons (e^–) accumulate along the ETC because O₂ is absent. Reoxygenation then causes a burst of ROS generation from multiple sites, resulting in lethal activation of the mitochondrial permeability transition pore.

ETC: Electron transport chain; ROS: Reactive oxygen species.

Reprinted by permission from [24] © Macmillan Publishers Ltd, Nature Medicine (2013).

Figure 5.  Inhaled NO is a selective-pulmonary vasodilator with actions on the systemic vasculature.

A schematic of an alveolar-capillary unit is presented highlighting the ability of inhaled NO to dilate pulmonary arterioles and reduce PAP. Although inhaled NO does not dilate systemic arterioles or alter SAP, inhaled NO does have systemic effects mediated by circulating cells exposed to NO in the lungs and blood-borne NO derivatives.

PAP: Pulmonary artery pressure; SAP: Systemic arterial pressure.

(A) Reprinted with permission from [29] © European Society of Cardiology (2007).

(B) Reprinted with permission from [27] © American Heart Association (2004).

Figure 6.  Kaplan–Meier survival curves for inhaled nitric oxide therapy over 4 year follow-up period by indication for inhaled nitric oxide use.

Survival for OHT and OLT patients treated for pulmonary hypertension was far greater than survival in medical patients treated for life-threatening hypoxemia (p = 0.001).

OHT: Orthotopic heart transplantation; OLT: Orthotopic lung transplantation; PHTN: Pulmonary hypertension; Pre-cap: Precapillary; RVF: Right ventricular failure; VAD: Ventricular assist device.

Reprinted with permission from [28] © Elsevier (2006).

Figure 7.  Vascular procedures damage the endothelial lining leading to decreased production of nitric oxide required for vascular homeostasis.

This results in thrombus formation and neointimal hyperplasia with subsequent stenosis.

VSMC: Vascular smooth muscle cell.

Reproduced with permission from [34] © The Royal Society of Chemistry (2012).

Van’t Hof RJ , RalstonSH. Nitric oxide and bone. Immunology103(3), 255–261 (2001).

 PubMed Web of Science ®Google Scholar

Witte MB , BarbulA. Role of nitric oxide in wound repair. Am. J. Surg.183(4), 406–412 (2002).

 PubMed Web of Science ®Google Scholar

Han G , NguyenLN, MacherlaCet al. Nitric oxide-releasing nanoparticles accelerate wound healing by promoting fibroblast migration and collagen deposition. Am. J. Pathol.180(4), 1465–1473 (2012).

 PubMed Web of Science ®Google Scholar

Schumacker PT . Nitric oxide quenches the fire in heart mitochondria. Nat. Med.19(6), 666–667 (2013).

 PubMed Web of Science ®Google Scholar

Bloch KD , IchinoseF, RobertsJDJr, ZapolWM. Inhaled NO as a therapeutic agent. Cardiovasc. Res.75(2), 339–348 (2007).

 PubMed Web of Science ®Google Scholar

Ichinose F , RobertsJDJr, ZapolWM. Inhaled nitric oxide: a selective pulmonary vasodilator: current uses and therapeutic potential. Circulation109(25), 3106–3111 (2004).

 PubMed Web of Science ®Google Scholar

George I , XydasS, TopkaraVKet al. Clinical indication for use and outcomes after inhaled nitric oxide therapy. Ann. Thorac. Surg.82(6), 2161–2169 (2006).

 PubMed Web of Science ®Google Scholar

Carpenter AW , SchoenfischMH. Nitric oxide release: part II. Therapeutic applications. Chem. Soc. Rev.41(10), 3742–3752 (2012).

 PubMed Web of Science ®Google Scholar