Evaluation of neural reflex activation as a potential mode of action for respiratory and cardiovascular effects of fine particulate matter

Figures & data

Figure 1. Proposed mode of action of neural reflex activation for both respiratory and cardiovascular effects following PM_2.5 exposure.

Table 1. Experimental animal studies of respiratory effects with vagal nerve manipulation.

Reference	Animal Model	N	PM2.5 Exposure	Exposure Concentration	Exposure Duration	Exposure Route	Vagal Manipulation Technique	Respiratory Response to PM2.5 Exposure	Result of Vagal Manipulation	P value
McQueen et al. (2007)	Anesthetized Wistar rats	9	DEPs	500 μg	Once	Intratracheal instillation	Bilateral vagotomy	Increased RMV	Prevention of PM-induced increase	< 0.05
		8						Increased BAL neutrophilia	Prevention of PM-induced increase	< 0.05
Lin et al. (2010)	Anesthetized SD rats	6	Cigarette smoke	6 mL of 100% cigarette smoke	Within 3 breaths	Inhalation	Bilateral vagotomy	Increased bradypnea	Prevention of PM-induced increase	< 0.05

Notes. BAL: Bronchoalveolar Lavage; DEPs: Diesel Exhaust Particles; PM: Particulate Matter; RMV: Respiratory Minute Volume; SD: Sprague Dawley.

Table 2. Experimental Animal studies of respiratory effects with pharmacological pretreatment.

Reference	Animal Model	N	PM2.5 Exposure	Exposure Concentration	Exposure Duration	Exposure Route	Pharmacological Treatment	Respiratory Response to PM2.5 Exposure	Result of Treatment	P value
Bergren et al. (2000)	OVA-sensitized Hartley guinea pigs	10–12	Cigarette smoke	5.3 ± 0.1 mg/L (5,300,000 μg/m^3)	30 min per day for 120 – 156 days	Inhalation	Intravenous capsaicin	Enhanced capsaicin-induced increase in C-fiber impulses	Increased C-fiber impulses	< 0.05
								Enhanced capsaicin-induced increase in airway hyperresponsiveness	Increased airway hyperresponsiveness	< 0.05
							Aerosolized capsaicin	Enhanced capsaicin-induced increase in C-fiber impulses	Increased C-fiber impulses	< 0.05
								Enhanced capsaicin-induced increase in airway hyperresponsiveness	Increased airway hyperresponsiveness	< 0.05
Wong et al. (2003)	F344/N rats	6	DEPs	632.9 ± 47.6 μg/m	4 h/ day, 5 days/week for 3 weeks	Inhalation via nose-only exposure chamber	Intraperitoneal capsaicin	Increased plasma extravasation	Exacerbation of PM-induced increase	< 0.05
		4–6						Increased respiratory tract inflammation	Decreased PM-induced inflammation	0.011
		6		35.3 ± 4.9 μg/m^3				Increased plasma extravasation	Exacerbation of PM-induced increase	<0.05
		4–6						No effect on respiratory tract inflammation	No change	NR
		6		NR		Inhalation of diesel engine room air		No effect on plasma extravasation	Increased extravasation compared to PM exposure	< 0.05
		4–6						No effect on respiratory tract inflammation	No change	NR
McQueen et al. (2007)	Anesthetized Wistar rats	3	DEPs	500 μg	Once	Intratracheal instillation	Atropine	Increased RMV	Prevention of PM-induced increase	NR
Lin et al. (2010)	Anesthetized SD rats	6	Cigarette smoke	6 mL of 100% cigarette smoke	Within 3 breaths	Inhalation	Perivagal capsaicin	Increased BAL neutrophilia	Prevention of PM-induced increase	< 0.05
							NAC		Prevention of PM-induced increase	< 0.05
							HC-030031		Prevention of PM-induced increase	< 0.05
							Iso-PPADS		Prevention of PM-induced increase	< 0.05
Lv et al. (2016)	Hartley guinea pigs	8	PM2.5	80 mg/kg	Once per day for three weeks	Intranasal instillation	Microinjected capsaicin	Increased cough reflex sensitivity	Exacerbation of PM-induced increase	< 0.05
							CPZ		Attenuation of PM-induced increase	< 0.05
				320 mg/kg			Microinjected capsaicin	Increased cough reflex sensitivity	Exacerbation of PM-induced increase	< 0.05
							CPZ		Attenuation of PM-induced increase	< 0.05
								Increased airway inflammation	Prevention of PM-induced increase	NR
								Increased airway hyperpermeability	Attenuation of PM-induced increase	NR
Robinson et al. (2018)	Anesthetized guinea pigs	3–7	DEP-OE	1 μg/mL	Once	Aerosolized exposure to vagus nerve	Janssen 130	Increased activation of vagus nerve	Prevention of PM-induced increase	< 0.05
							Xention D0501		No change	> 0.05
							GSK2193874		No change	> 0.05
							NAC		Prevention of PM-induced increase	< 0.05
				10 μg/mL	Once		Janssen 130	Increased tracheal pressure	Prevention of PM-induced increase	< 0.05
Xu et al. (2019)	C57Bl/6N mice	8	PM2.5	7.8 mg/kg	Once per day for 2 days	Intranasal instillation	AMG9810	Increased bronchial responsiveness	Prevention of PM-induced increase	< 0.001
								Increased airway resistance	Prevention of PM-induced increase	< 0.01
								Increased airway inflammation	Attenuation of PM-induced increase	< 0.01
								Increased lung oxidative stress (MDA levels)	Prevention of PM-induced increase	< 0.05
								Increased lung tissue hydrogen peroxide	No change	> 0.05
							A967079	Increased bronchial responsiveness	Prevention of PM-induced increase	< 0.001
								Increased airway resistance	Prevention of PM-induced increase	< 0.001
								Increased airway inflammation	Attenuation of PM-induced increase	< 0.001
								Increased lung oxidative stress (MDA levels)	Prevention of PM-induced increase	< 0.01
								Increased lung tissue hydrogen peroxide	Prevention of PM-induced increase	< 0.001
							AMG9810 + A967079	Increased bronchial responsiveness	Prevention of PM-induced increase	< 0.01
								Increased airway resistance	Prevention of PM-induced increase	< 0.05
								Increased airway inflammation	Attenuation of PM-induced increase	< 0.001
								Increased lung oxidative stress (MDA levels)	Prevention of PM-induced increase	< 0.001
								Increased lung tissue hydrogen peroxide	No change	> 0.05
Lian et al. (2022)	OVA-sensitized Balb/c mice	6	PM2.5 + ozone	20 μg PM2.5 and 0.5 ppm ozone	Once per day, every 3 days, 3 times total	Intratracheal instillation	CPZ	Increased allergic inflammation (lung inflammatory cells)	Prevention of PM-induced increase	< 0.01
								Increased lung oxidative stress (MDA and 8-OhdG levels)	Prevention of PM-induced increase	< 0.01
								Increased airway hyperresponsiveness	Prevention of PM-induced increase	< 0.01

Notes. BAL: Bronchoalveolar Lavage; CPZ: Capsazepine; DEPs: Diesel Exhaust Particles; DEP-OE: Diesel Exhaust Particles Organic Extract; MDA: Malondialdehyde; NAC: N-acetylcysteine; NR: Not Reported; OVA: Ovalbumin; PM: Particulate Matter; RMV: Respiratory Minute Volume; SD: Sprague Dawley.

Table 3. Experimental animal studies of cardiovascular effects with vagal nerve manipulation.

Reference	Animal Model	N	PM2.5 Exposure	Exposure Concentration	Exposure Duration	Exposure Route	Vagal Manipulation Technique	Cardiovascular Response to PM2.5 Exposure	Result of Vagal Manipulation	P Value
Matran et al. (1990)	Anesthetized pigs	5	Cigarette smoke	NR	2 min	Inhalation by respirator	Bilateral vagotomy	Decreased vascular resistance in bronchial artery	No change	NR
McQueen et al. (2007)	Anesthetized Wistar rats	7–10	DEPs	500 μg	Once	Intratracheal instillation	Bilateral vagotomy	No effect on BP, HR, or HRV	No change	> 0.05
Hazari et al. (2011)	Spontaneously hypertensive rats	5–6	DE	150 μg/m^3	4 h	Inhalation	Bilateral vagotomy	Increased sensitivity to arrhythmia (from aconitine challenge)	Slight attenuation of PM-induced increase	> 0.05
								Increased HR	Exacerbation of PM-induced increase	< 0.05
								Increased HRV	Prevention of PM-induced increase (except for increased LF/HF ratio)	< 0.05
								Increased QRS duration	Prevention of PM-induced increase	< 0.05
								Decreased ST segment duration	No change	> 0.05
Carll et al. (2013)	Spontaneously hypertensive heart failure rats	5	DE	500 μg/m^3	4 h	Inhalation	Bilateral vagotomy	No effect on cardiac contractility	Increased cardiac contractility	< 0.05
								Slowed left ventricle relaxation	No change
								No effect on HR	Increased HR

Notes. BP: Blood Pressure; DE: Diesel Exhaust; DEPs: Diesel Exhaust Particles; HR: Heart Rate; HRV: Heart Rate Variability; LF/HF: Low Frequency/High Frequency; NR: Not Reported; PM: Particulate Matter.

Table 4. Experimental animal studies of cardiovascular effects with pharmacological pretreatment.

Reference	Animal Model	N	PM2.5 Exposure	Exposure Concentration	Exposure Duration	Exposure Route	Pharmacological Treatment	Cardiovascular Response to PM2.5 Exposure	Result of Treatment	P Value
Matran et al. (1990)	Pigs	5–6	Cigarette smoke	NR	2 min	Inhalation via nasal tube	Atropine	Decreased vascular resistance in nasal cavity sphenopalatine artery	No change	NR
							Lignocaine		No change	NR
							Subcutaneous capsaicin		No change	NR
							Atropine	Decreased vascular resistance in superior laryngeal artery	No change	NR
							Lignocaine		No change	NR
							Subcutaneous capsaicin		No change	NR
							Atropine	Decreased vascular resistance in bronchial artery	No change	NR
							Lignocaine		No change	NR
							Subcutaneous capsaicin		No change	NR
McQueen et al. (2007)	Anesthetized Wistar rats	4–10	DEPs	500 μg	Once	Intratracheal instillation	Atropine	No effect on BP, HR, or HRV	No change	> 0.05
Ghelfi et al. (2008)	SD rats	24	CAPs	Mean PM2.5 mass concentration: 218 ± 23 mg/m^3	5 h	Inhalation	CPZ	Increased cardiac oxidative stress	Prevention of PM-induced increase	NR
		8			5 h per day for 4 months			Increased oxidative lipids in heart tissue	Prevention of PM-induced increase	NR
								Increased cardiac edema	Prevention of PM-induced increase	NR
								Decreased HR	Prevention of PM-induced decrease	NR
Lin et al. (2010)	Anesthetized SD rats	6	Cigarette smoke	6 mL of 100% cigarette smoke	Within 3 breaths	Inhalation	Perivagal capsaicin	Transient increase in HR	Attenuation of PM-induced increase	< 0.05
		6–8						Transient increase in arterial BP	Attenuation of PM-induced increase	< 0.05
							NAC	Transient increase in HR	Attenuation of PM-induced increase	< 0.05
								Transient increase in arterial BP	Attenuation of PM-induced increase	< 0.05
							HC030031	Transient increase in HR	Attenuation of PM-induced increase	< 0.05
								Transient increase in arterial BP	Attenuation of PM-induced increase	< 0.05
							Iso-PPADS	Transient increase in HR	Attenuation of PM-induced increase	< 0.05
								Transient increase in arterial BP	Attenuation of PM-induced increase	< 0.05
Hazari et al. (2011)	Spontaneously hypertensive rats	5–6	DE	150 μg/m^3	4 h	Inhalation	HC030031	Increased sensitivity to arrhythmia (from aconitine challenge	Prevention of PM-induced increase	< 0.05
							Ruthenium red		Prevention of PM-induced increase	< 0.05
							SB366791		Attenuation of PM-induced increase	< 0.05
							Atropine		No change	> 0.05
							HC030031	Increased HR	Prevention of PM-induced increase	NR
							Ruthenium red		No change	NR
							SB366791		No change	NR
							Atropine		No change	NR
							HC030031	Increased HRV	No change	> 0.05
							Ruthenium red		No change	> 0.05
							SB366791		No change	> 0.05
							Atropine		Prevention of PM-induced increase	< 0.05
							HC030031	Increased QRS duration	Prevention of PM-induced increase	< 0.05
							Ruthenium red		Prevention of PM-induced increase	< 0.05
							SB366791		Prevention of PM-induced increase	< 0.05
							Atropine		Prevention of PM-induced increase	< 0.05
							HC030031	Decreased ST segment duration	Prevention of PM-induced increase	< 0.05
							Ruthenium red		Prevention of PM-induced increase	< 0.05
							SB366791		Prevention of PM-induced increase	NR
							Atropine		No change	NR
Carll et al. (2013)	Spontaneously hypertensive heart failure rats	4–9	DE	500 μg/m^3	4 h	Inhalation	Atropine	Increased HR (during exposure)	No change	> 0.05
		5–9					Atenolol		Prevention of PM-induced increase	< 0.05
							Atropine	Increased BP (during exposure)	No change	> 0.05
							Atenolol		Prevention of PM-induced increase	< 0.05
							Atropine	Increased contractility (during exposure)	No change	> 0.05
							Atenolol		Prevention of PM-induced increase	< 0.05
							Atropine	No change in HR (treadmill test 4-hr post-exposure)	No change	> 0.05
							Atenolol		Decreased HR	< 0.05
							Atropine	Increased SDNN (treadmill test 4-hr post-exposure)	No change	> 0.05
							Atenolol		No change	> 0.05
							Atropine	Increased RMSSD (treadmill test 4-hr post-exposure)	No change	> 0.05
							Atenolol		No change	> 0.05
							Atropine	No change in LF/HF ratio (treadmill test 4-hr post-exposure)	No change	> 0.05
							Atenolol		No change	> 0.05
Robertson et al. (2014)	Anesthetized Wistar rats	4–5	DEPs	0.5 mg	6 h	Intratracheal Instillation	AMG 9810	Increased BP	Attenuation of PM-induced increase	< 0.05
								Increased duration of arrhythmias	Attenuation of PM-induced increase	NR
		NR						Increased infarct size after reperfusion injury in vivo	Prevention of PM-induced increase	< 0.01
		3–5						Increased cardiomyocyte apoptosis	Prevention of PM-induced increase	NR
								Decreased cardiomyocyte viability	Prevention of PM-induced decrease	< 0.01

Notes. BP: Blood Pressure; CAPs: Concentrated Ambient Particles; CPZ: Capsazepine; DE: Diesel Exhaust; DEPs: Diesel Exhaust Particles; HR: Heart Rate; HRV: Heart Rate Variability; LF/HF: Low Frequency/High Frequency; NR: Not Reported; PM: Particulate Matter; RMSSD: Square Root of the Mean of Squared Differences of Adjacent RR Intervals; SD: Sprague Dawley; SDNN: Standard Deviation of the RR Interval.

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Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.