Oxidative Stress and Lung Fibrosis: Towards an Adverse Outcome Pathway

Area of Science:

• Pulmonary Medicine
• Toxicology
• Cellular Biology

Background:

• Lung fibrosis is a fatal, progressive disease driven by abnormal lung epithelial cell healing.
• Persistent lung injury, characterized by oxidative stress and chronic inflammation, is central to fibrosis development.
• Chronic cigarette smoking is a significant risk factor for lung fibrosis due to its oxidative stress-inducing properties.

Purpose of the Study:

• To develop an adverse outcome pathway (AOP) framework for investigating lung fibrosis mechanisms.
• To elucidate the pathway from lung injury caused by inhaled toxicants, such as cigarette smoke, to fibrosis.
• To provide a mechanistic understanding of how persistent oxidative stress leads to lung fibrosis.

Main Methods:

• Literature review and weight of evidence synthesis to establish the AOP.
• Identification of a molecular initiating event (MIE): oxidative stress.
• Definition of key events (KEs) in the pathway: mediator secretion, inflammatory cell recruitment, fibroblast activation, and extracellular matrix deposition.

Main Results:

• Oxidative stress is proposed as the MIE, leading to increased proinflammatory and profibrotic mediators (KE1).
• These mediators trigger inflammatory cell recruitment (KE2), followed by fibroblast proliferation and myofibroblast differentiation (KE3).
• Increased extracellular matrix deposition (KE4) ultimately results in lung fibrosis.

Conclusions:

• The developed AOP provides a mechanistic framework for understanding lung fibrosis.
• It links molecular events like oxidative stress to cellular and tissue-level changes culminating in fibrosis.
• This AOP can aid in evaluating the role of inhaled toxicants, including cigarette smoke, in driving lung fibrosis.