Particulate matter-induced lung inflammation increases systemic levels of PAI-1 and activates coagulation through...

Area of Science:

• Environmental Health
• Cardiovascular Research
• Immunology

Background:

• Ambient particulate matter (PM) exposure is a significant contributor to cardiovascular mortality.
• Previous studies linked PM exposure to a prothrombotic state mediated by IL-6 from alveolar macrophages.
• The role of plasminogen activator inhibitor-1 (PAI-1), a key thrombolysis regulator, in PM-induced prothrombosis was investigated.

Purpose of the Study:

• To determine if PM exposure increases PAI-1 levels in mice.
• To elucidate the mechanisms, specifically the involvement of IL-6 and TNF-α, linking PM exposure to PAI-1 regulation and prothrombotic states.

Main Methods:

• Mice were exposed to concentrated ambient PM (CAPs) or urban PM via inhalation or intratracheal instillation.
• Control groups received filtered air or PBS.
• PAI-1 mRNA and protein levels were measured in lung and adipose tissue.
• Intervention with etanercept (TNF-α inhibitor) was performed.
• Coagulation activation and thrombus formation tendency were assessed.

Main Results:

• PM exposure increased IL-6-dependent coagulation activation both locally in the lung and systemically.
• PAI-1 mRNA and protein levels were elevated in mice exposed to PM compared to controls.
• The increase in PAI-1 was similar in wild-type and IL-6 knockout mice, indicating IL-6 independence.
• Etanercept treatment abolished the PM-induced PAI-1 increase, demonstrating TNF-α dependence.
• Etanercept did not prevent PM-induced thrombus formation.

Conclusions:

• Inhaled PM exposure leads to a TNF-α-dependent increase in PAI-1.
• PM exposure also causes an IL-6-dependent activation of coagulation.
• These findings suggest that distinct mechanisms mediate the link between PM-induced lung inflammation and the development of a prothrombotic state.