Table 2.

The effects of particulate matter on inflammation, oxidative stress, blood parameters, and hemostatic changes: Evidence from in vivo studies.

Models	Exposure/Method	Results			Interpretation	References
		Inflammation and Oxidative Stress	Coagulation and Adhesion Molecules	Blood Parameters
Male Wistar rats 10–12 wk-old Cisplatin-induced AKI rats	Intratracheal instillation of Cerium oxide nanoparticles (CeO2 NPs) 1 mg/kg	Normal rats: # Kidney ↑ TNF-α, IL-6, GSH ↑ DNA damage # Lung tissue ↔ TNF-α, IL-6 ↓ catalase activity AKI rats: # Kidney ↑ TNF-α, IL-6, GSH ↑ DNA damage # Lung tissue ↑ TNF-α, IL-6 ↓ catalase activity			Pulmonary exposure to CeO2 NPs induced inflammation and oxidative stress, and damaged DNA in the kidney. These effects were enhanced in kidney injury models.	[57]
Male mice C57Bl6/j 8–12 wk-old IL-6+/+ IL-6−/−	Inhalation exposure to concentrated ambient particles (CAPs) from downtown Chicago for 8 h/d for 3 d Evaluate at 24 h after exposure	# IL-6+/+ vs. non-PM): Lung tissue ↑ IL-6/18s mRNA ↑ SP-B/18s mRNA BALF ↑ IL-6 ↑ TNF-α ↑ MCP-1 # IL-6−/−: Lung tissue ↓ IL-6/18s mRNA ↓ SP-B/18s mRNA BALF ↓ IL-6 ↔ TNF-α ↔ MCP-1	# IL-6+/+ vs. non- PM): Lung tissue ↑ TF/18s mRNA Plasma ↑ TAT complexes White adipose tissue ↑ PAI-1/18s mRNA # IL-6−/−: Lung tissue ↓ TF/18s mRNA Plasma ↓ TAT complexes White adipose tissue ↔ PAI-1/18s mRNA		Exposure to all types of PM could activate inflammatory response, coagulation system and inhibit fibrinolysis, resulting in a prothrombotic state. PM-induced coagulation through IL-6 production and blocking IL-6 signaling could alleviate the thrombotic process.	[56]
	Intratracheal instillation of urban PM (SRM1649a) 10, 100, 200 µg/animal Evaluate at 24 h after exposure	# IL-6+/+ vs. non- PM): BALF ↑ protein ↑ macrophage, PMN ↑ IL-6 (dose-dependent) ↑ TNF-α # IL-6−/−: BALF ↔ protein ↔ macrophage, PMN ↓ IL-6 ↔ TNF-α	# IL-6+/+ vs. non- PM): ↑ TF, ↑TF mRNA in lung tissue ↑ BALF D-dimer ↑ TAT complexes ↓ Bleeding time ↓ PT, ↓ PTT ↑ PAI-1/18s mRNA in the lung, adipose tissue ↑ PAI-1 in BALF # IL-6−/−: ↓ TF level, ↓TF mRNA in lung tissue ↓ BALF D-dimer ↓ TAT complexes ↔ PAI-1/18s mRNA in the lung, adipose tissue ↔ PAI-1 in BALF
Male mice (C57BL/6) 8–12 wk-old	Inhalation exposure to concentrated ambient particles (CAPs) from downtown Chicago for 8 h/d for 3 d	↑ NE in the lung, BAT, adrenal gland ↑ IL-6 in BALF	↑ TAT complexes ↑ thrombus formation ↓ thrombotic occlusion time		Inhalation of PM caused catecholamine release and promoted IL-6-mediated thrombosis.	[44]
Adrb1+/+Adrb2+/+ Adrb1−/−Adrb2+/+ Adrb1+/+Adrb2−/− Adrb1−/−Adrb2−/−	Intratracheal instillation of urban PM (SRM1649a) 200 µg/animal Evaluate at 24 h after exposure	BALF # Adrb1+/+Adrb2+/+ (vs. non-PM): ↑ IL-6 ↔ TNF-α, MCP-1 # Adrb1−/− Adrb2+/+ (vs. non-PM): ↑ IL-6 ↔ TNF-α, MCP-1 # Adrb1+/+Adrb2−/−: ↓ IL-6 ↔ TNF-α, MCP-1 # Adrb1−/−Adrb2−/−: ↓ IL-6 ↔ TNF-α, MCP-1	Plasma # Adrb1+/+Adrb2+/+ (vs. non-PM): ↑ TAT complexes ↓ thrombotic occlusion time # Adrb1−/− Adrb2+/+ (vs. non-PM): ↑ TAT complexes # Adrb1+/+Adrb2−/−: ↓ TAT complexes ↑ thrombotic occlusion time # Adrb1−/−Adrb2−/−: ↓ TAT complexes		β2AR encoded by the Adrb2 gene in alveolar macrophages was necessary for PM-induced upregulation of IL-6, and enhanced susceptibility to thrombotic events.
Adrb1+/+Adrb2+/+ Adrb1+/+Adrb2−/−	Inhalation exposure to concentrated ambient particles (CAPs) from downtown Chicago for 8 h/d for 3 d	# Adrb1+/+Adrb2−/−: ↓ IL-6/18s mRNA	# Adrb1+/+Adrb2−/−: ↓ TAT complexes ↓ TF
Lyms-Cre Adrb2flox/flox mice (macrophage-specific deletion of β2AR) vs. Adrb2flox/flox	Inhalation exposure to concentrated ambient particles (CAPs) from downtown Chicago for 8 h/d for 3 d Pretreated with formoterol (long-acting β2AR agonist) 1 × 10−5 M via inhalation twice every 12 h	BALF # Adrb2flox/flox without formoterol: ↑ IL-6 in BALF # Adrb2flox/flox with formoterol: ↑↑ IL-6 # Lyms-Cre Adrb2flox/flox: ↓ IL-6 # Lyms-Cre Adrb2flox/flox with formoterol: ↓ IL-6 (vs. Adrb2flox/flox) ↔ IL-6 (vs. without formoterol)	Plasma # Adrb2flox/flox without formoterol: ↑ TAT complexes ↑ factor II, TF mRNA ↓ thrombotic occlusion time # Adrb2flox/flox with formoterol: ↑ factor II, TF mRNA ↓ thrombotic occlusion time # Lyms-Cre Adrb2flox/flox: ↓ factor II, TF mRNA ↓ TAT complexes ↑ thrombotic occlusion time # Lyms-Cre Adrb2flox/flox with formoterol vs. Adrb2flox/flox: ↓ factor II, TF mRNA ↑ thrombotic occlusion time vs. without formoterol: ↔ factor II, TF mRNA ↔ thrombotic occlusion time
Male mice C57Bl6/j Old mice (20 mo-old) vs. Young mice (10 wk-old)	Inhalation of ambient PM2.5 and PM10 at the roadside tunnel for 25–26 d (A) tunnel-filtered (B) tunnel-exposed in urban roadside tunnel (C) control in clean facility	# Young mice (vs. non-PM): ↔ WBC in BALF # Old mice (vs. young mice) in clean air: ↑ WBC in BALF # Old mice (vs. young mice) with PM: ↔ WBC in BALF	# Young mice (vs. non-PM): ↔ lung vWF ↔ plasma vWF ↓ lung TM ↑ P-selectin ↔ PF4 # Old mice (vs. young mice) in clean air: ↑ lung VWF ↑ plasma VWF ↔ lung TM ↑ P-selectin ↔ PF4 # Old mice (vs. young mice) with PM: ↑ lung vWF ↔ plasma VWF ↔ lung TM ↔ P-selectin ↔ PF4	# Young mice (vs. non-PM): ↑ RBC, Hb ↑ platelets ↔ WBC # Old mice (vs. young mice) in clean air: ↑ RBC, Hb ↑ platelets ↑ WBC # Old mice (vs. young mice) with PM: ↔ RBC, Hb ↔ platelets ↔ WBC	Continuous inhalation of particulate matter air pollution triggered inflammatory response, and activated platelets, and endothelial cells. The older mice had higher inflammatory biomarkers at baseline, therefore the PM-mediated effects were not demonstrated in the old mice.	[59]
Male mice C57Bl6/j with spontaneous hypertension 11–12 wk-old	Intratracheal instillation particulate matter # Road tunnel dust (RTD): 0.3, 1, 3, and 10 mg/kg # Urban dust (EHC-93) from Environmental Health Center in Ottawa, Canada 10 mg/kg Evaluation of lung tissue at 4, and 48 h after PM exposure		# RTD (at 10 mg/kg): - at 4 h: ↑ TF ↑ thrombus formation - at 48 h: ↑ TF ↑↑ thrombus formation # EHC-93: - at 4 h: ↔ TF ↑ thrombus formation - at 48 h: ↑↑ TF ↑↑ thrombus formation		PM induced procoagulant activity in the lungs, via increased TF expression and aggravated thrombus formation.	[58]
Hamsters (Pfd Gold) 100–110 g	Intratracheal instillation of polystyrene particles: # 60 nm UFP -unmodified 500 μg/animal -carboxylated 500 μg/animal -amined 5, 50, 500 μg/animal # 400 nm: Amine-modified polystyrene particles 500 μg/animal Evaluation of BALF at 1 h after UFP exposure	# Unmodified and carboxylated UFP: ↔ PMN influx # Amine-UFP (60 nm): ↑ PMN influx (50 and 500 µg/animal) ↑ protein, histamine (500 μg/animal) # Amine-particles (400 nm): ↑ PMN influx ↑ BALF protein ↔ BALF histamine	# Unmodified and carboxylated UFP: ↔ thrombus formation # Amine-UFP (60 nm): ↑ thrombus formation (at 50 and 500 µg/animal) # Amine-particles (400 nm): ↔ thrombus formation		Exposure to both positively charged UFP (60 & 400 nm) resulted in inflammation in the respiratory tract, but only the UFP (60 nm) rapidly activated the clotting system within an hour, leading to thrombosis.	[51]
Hamster 100–110 g	Intratracheal instillation of polystyrene particles: # 60 nm UFP - unmodified 500 μg/animal - carboxylated 500 μg/animal - amined 5, 50, 500 μg/animal # 400 nm amined- polystyrene particles 500 μg/animal Evaluation of BALF at 1 h after UFP exposure	# Unmodified and carboxylated UFP: ↔ PMN influx # Amine-particles (60 nm and 400 nm): ↑ PMN influx (50 μg) ↑↑ PMN influx (500 μg)	# Unmodified and carboxylated UFP: ↔ thrombus formation # Amine-particles (60 nm): ↑↑ thrombus formation (50 μg) ↑ thrombus formation (500 μg) # Amine-particles (400 nm): ↔ thrombus formation		UFP induced pulmonary inflammation and promoted thrombosis, but the degree of lung inflammation did not show a correlation with the extent of thrombosis.	[60]
	Intratracheal instillation of DEP (SRM 1650) 5, 50, 500 μg/animal Evaluate at 1 h after UFP exposure	BALF ↑ PMN influx ↑ protein ↑ histamine (at 50 and 500 μg/animal)	↑ thrombus formation (50 μg) ↑↑ thrombus formation (500 μg) ↓ PFA100 closure time		DEP exposure activated platelet and thrombin generation, leading to thrombosis.
Female mice (C57BL/6) 8–10 wk-old sex-age-matched Sirt1 +/+ Sirt1 −/− Sirt1 overexpression in WT mice (vs. WT mice)	Intranasal instillation of PM2.5 (SRM 8785) 100 µg/animal for 24 h	# Sirt1 +/+: ↑ lung NF-ĸB ↑ BALF albumin, PMN ↑ BALF TNF-α & IL-6 # Sirt1 −/−: ↑↑ lung NF-κB ↑↑ BALF albumin, PMN ↑↑ BALF TNF-α & IL-6	# Sirt1 +/+: ↑ lung fibrin formation ↓ TFPI ↑ TF ↑ lung PAI-1 ↔ plasma PAI-1 ↓ lung TM # Sirt1 −/−: ↑ ↑ lung fibrin formation ↓ ↓ TFPI ↑ TF ↑ ↑ lung PAI-1 ↔ plasma PAI-1 ↓↓ lung TM # Sirt1 overexpression: ↓ lung fibrin formation ↑ lung TM		PM2.5 exposure promoted pulmonary vascular injury and enhanced inflammation, coagulation, and inhibited fibrinolysis, which was regulated by Sirt1 and NF-κB pathways.	[53]
Male SD rats 8–12 wk-old	Intratracheal instillation of PM2.5 once every 3 d for 30 d Doses: - Low dose: 1.8 mg/kg - Middle dose: 5.4 mg/kg - High dose: 16.2 mg/kg PM2.5 was collected from central Beijing, China	↑ Alveolar wall thickening ↑ IL-6, IL-1β, CRP ↔ MCP-1	↓ Aortic valve peak blood flow ↑ thrombus formation ↑ TF ↑ TAT complexes ↑ Factor Xa ↑↑ D-dimer ↓ TM ↔ TFPI ↑ tPA ↓ vWF ↑ PT, PTT, TT ↔ fibrinogen ↑↑ ICAM-1, VCAM-1	↓ platelets	PM2.5 induced vascular endothelial injury, systemic inflammatory response, altered coagulation factors, anticoagulant pathway, and fibrinolytic system, resulting in the prothrombotic state, and DIC.	[54]
Male Wistar Kyoto (WKY) rats 12–15 wk-old	Intratracheal instillation of PM2.5 and PM10 from The Northern and Southern Mexico - Total fraction - Insoluble fraction - Soluble fraction (control) of each PM2.5 and PM10 3.3 mg/kg Evaluation at 24 or 72 h after PM exposure	# Total fraction and insoluble fraction of PM2.5 & PM10: ↑ BALF cell count ↓ alveolar macrophages Lung tissue ↑ total protein, ↑ albumin, ↓ ascorbic acid ↑ MIP-2, TNF-α mRNA ↑ BALF MIP-2, TNF-α ↑ HO-1 ↑ LOX-1R, ↑ NOS	# Total fraction and insoluble fraction of PM2.5 & PM10: ↑ lung TF mRNA ↓ tPA mRNA ↑ PAI-1 mRNA	# Total fraction and insoluble fraction of PM2.5 & PM10: ↔ RBC, Hb, Hct, platelet, and WBC	Exposure to PM aggravated pulmonary inflammation and oxidative stress, as well as disruption in the procoagulant and fibrinolytic pathways of the lung.	[55]
Male mice (C57BL/6) 8–12 wk-old IL-6+/+ IL-6−/− IL-6+/+ depleted alveolar macrophages	Intratracheal instillation of PM10 from ambient air in Düsseldorf, Germany 10 μg/animal for 24 h # Pretreated with Intratracheally instillation of liposomal clodronate 120 mg/animal for 48 h before PM exposure (Setting of WT mice depleted of alveolar macrophages)	BALF # IL-6+/+ vs. non-PM10: ↑ macrophage, PMN ↑ IL-6, TNF-α, IFN-γ ↔ MCP-1, IL-10, IL-12 # IL-6−/− vs. non-PM10: ↑ macrophage, PMN ↔ IL-6 ↑ TNF-α ↔ MCP-1, IL-10, IL-12, IFN-γ # IL-6−/− vs. IL-6+/+: ↓ IL-6 ↔ TNF-α, MCP-1, IL-10, IL-12, IFN-γ # IL-6+/+ depleted alveolar macrophages: ↓ macrophage ↔ PMN ↓ IL-6 ↔ TNF-α, MCP-1, IL-10, IL-12, IFN-γ	Plasma # IL-6+/+ vs. non-PM10: ↑ Factor II, VIII, X ↑ Fibrinogen ↓ Bleeding time ↓ PT, ↓ PTT ↓ thrombotic occlusion time ↑ TAT complexes # IL-6−/− vs. non-PM10: ↔ Factor VIII ↔ Bleeding time ↔ PT, ↔ PTT ↔ thrombotic occlusion time ↔TAT complexes # IL-6+/+ depleted alveolar macrophages: ↓ Factor VIII ↑ Bleeding time ↑ PT, ↑ PTT ↓ TAT complexes ↑ thrombotic occlusion time	# IL-6+/+ vs. non-PM10: ↑ Platelet # IL-6−/− vs. non-PM10: ↔ Platelet # IL-6+/+ depleted alveolar macrophages: ↓ Platelet	PM10 exposure-induced pulmonary inflammation, and IL-6 release. IL-6 was the key mediator, which enhanced coagulation factor function, resulted in shortening of clotting time, and led to thrombosis. Blocking either the macrophage function or IL-6 signal could alleviate PM-induced prothrombotic state.	[52]

AKI: acute kidney injury, BALF: bronchoalveolar lavage fluid, BAT: brown adipose tissue, β₂AR: adrenergic receptor beta-2, CAPs: concentrated ambient particles, CeO₂ NPs: Cerium oxide nanoparticles, CRP: C-reactive protein, d: days, DEP: diesel exhaust particles, DIC: disseminated intravascular coagulopathy, DNA: deoxyribonucleic acid, EHC-93: Environmental health center-93, GSH: glutathione, h: hours, Hb: hemoglobin, Hct: hematocrit, HO-1: heme oxygenase-1, ICAM-1: intercellular adhesion molecule-1, IL-1β: interleukin-1beta, IL-6: interleukin-6, IL-10: interleukin-10, IL-12: interleukin-12, IFN-g: interferon-g, LOX-1R: lectin-like oxidized low-density lipoprotein receptor-1, MCP-1: monocyte chemoattractant protein-1, MIP-2: macrophage inflammatory protein-2, mo: months, mRNA: messenger ribonucleic acid, NE: norepinephrine, NF-κB: nuclear factor-κB, NOS: nitric oxide synthase, PAI-1: plasminogen activator inhibitor-1, PFA100: platelet function analyzer-100, PF4: platelet factor 4, PM: particulate matter, PM_2.5: particulate matter in diameter <2.5 µm, PM₁₀: particulate matter in diameter <10 µm, PMN: polymorphonuclear cells, PT: prothrombin time, PTT: activated partial thromboplastin time, RBC: red blood cells, RTD: road tunnel dust, SD rats: Sprague-Dawley rats, SP-B: surfactant protein B, SRM: standard reference material, TAT complexes: thrombin-antithrombin complexes, TF: tissue factor, TFPI: tissue factor pathway inhibitor, TM: thrombomodulin, TNF-α: tumor necrotic factor-α, tPA: tissue plasminogen activator, TT: thrombin time, UFP: ultrafine particle, VCAM-1: vascular cell adhesion molecule-1, VWF: von Willebrand factor, WBC: white blood cells, wk: week, WT mice: wild type mice.