nitric_oxide

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Nitric Oxide

Nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) in M1 macrophages and neutrophils during the inflammatory phase of wound healing. NO has a very short half-life (seconds to minutes in tissue), modeled as a high decay rate. It serves three functional roles: vasodilation (increases local perfusion), antimicrobial activity (suppresses biofilm growth via reactive nitrogen species), and anti-fibrotic signaling (reduces excessive collagen deposition).

Biology

Nitric oxide is a small gaseous signaling molecule produced by the inducible isoform of nitric oxide synthase (iNOS) in activated immune cells. During the inflammatory phase, M1 macrophages are the primary source, with neutrophils contributing at a lower rate (Witte and Barbul 2002). M2 macrophages do not express iNOS and therefore do not produce NO.

NO mediates vasodilation by activating soluble guanylyl cyclase in vascular smooth muscle cells, increasing cyclic GMP and causing relaxation. In wounds, this increases local perfusion and oxygen delivery to the healing tissue (Luo and Chen 2005). NO also serves as a direct antimicrobial effector: reactive nitrogen species (peroxynitrite, nitrogen dioxide) generated from NO are toxic to bacteria and suppress biofilm growth (Fang 1997).

In the later phases of healing, NO exerts an anti-fibrotic effect by reducing collagen deposition. NO donors decrease collagen synthesis and scar formation in wound models (Schaffer et al. 1996), providing a natural brake on excessive fibrosis during the inflammatory phase.

In diabetic wounds, iNOS expression is reduced by approximately 40%, contributing to impaired healing through diminished vasodilation, weakened antimicrobial defense, and loss of anti-fibrotic regulation (Witte et al. 2002).

Model

Single diffusing continuum field with rapid decay representing the short-lived nature of NO in tissue.

NO production:

• M1 macrophages produce NO at m1_production rate, tapered by M1 state age (declining iNOS expression over time)
• Neutrophils produce NO at neutrophil_production rate, tapered by cell age
• In diabetic mode, production rates are multiplied by diabetic.no_factor (approximately 0.6, representing 40% reduction in iNOS expression)
• Production uses agent-level deposition via ScaledGrid

NO decay:

• High PDE decay rate (0.05) models rapid autoxidation (seconds to minutes half-life)
• Fast diffusion (0.02) reflects the small gaseous molecule crossing cell membranes freely

Downstream effects (consumed by other modules):

• Vasodilation: angiogenesis source hook boosts effective perfusion by angio_rate * vasodilation_factor * NO in wound voxels
• Antimicrobial: biofilm post hook scales effective growth rate by max(0, 1 - antimicrobial_factor * NO)
• Anti-fibrotic: fibroblast behavior scales collagen deposition by max(0, 1 - collagen_suppression * NO)

Parameters

From modules/nitric_oxide/config.toml and sim_param.h:

Parameter	Default	Units	Description	Source
enabled	true	bool	Master switch	Convention
diffusion	0.02	-	Fast diffusion (small gaseous molecule)	Calibrated
decay	0.05	per step	Rapid autoxidation (half-life seconds to minutes)	Calibrated
m1_production	0.01	per step	iNOS-derived NO from M1 macrophages	Witte and Barbul 2002 (DOI)
neutrophil_production	0.005	per step	iNOS-derived NO from neutrophils	Witte and Barbul 2002 (DOI)
vasodilation_factor	0.05	multiplier	Perfusion boost per unit NO	Luo and Chen 2005 (DOI)
antimicrobial_factor	0.3	multiplier	Biofilm growth suppression per unit NO	Calibrated
collagen_suppression	0.03	multiplier	Anti-fibrotic collagen deposition reduction	Schaffer et al. 1996 (DOI)

Coupling

Reads

Field	Source module	How used
(Agent positions)	immune	M1 macrophages and neutrophils deposit NO at their locations via iNOS

Writes

Field	Consumer modules	What is written
NitricOxide	angiogenesis (vasodilation boost), biofilm (antimicrobial suppression), fibroblast (collagen suppression)	iNOS production from M1 macrophages and neutrophils

Source files

File	Purpose
nitric_oxide_pde.h	NO diffusion field: fast diffusion, high decay (starts at 0, produced by immune cells)
params.h	NitricOxideParams struct (enabled flag; remaining params in sim_param.h)
config.toml	Module configuration