This AOP describes the linkages between the interaction of substances with the cellular membrane components and the lung fibrosis. Lung fibrosis is a dysregulated or an exaggerated tissue repair process. It denotes the presence of scar tissue in the alveolar capillary region of the lung where gas exchange occurs; it can be localised or more diffuse involving bronchi and pleura. The process involves intricate dynamics between several inflammatory and immune response cells, and the microenvironment of the alveolar-capillary membrane consisting of both immune and non-immune cells, and the lung interstitium, in the presence of sustained or repeated toxicant stimuli. Regardless of the type of stimulus, the interaction between the substance and components of the cellular membrane leading to release of danger signals/alarmins marks the first event, which is a molecular initiating event (MIE) in the process of tissue repair. As a consequence, a myriad of proinflammatory mediators are secreted (KE1) that signal the recruitment of proinflammatory cells into the lungs (KE2). The MIE, KE1 and KE2 represent the same functional changes that are collectively known as inflammation, the purpose of which is to clear the invading pathogen or toxic substance. In the presence of continuous stimulus or persistent toxic substances, tissue injury ensues leading to the alveolar capillary membrane integrity loss (KE3) and activation of adaptive immune response. The purpose of the adaptive immune response is to resolve the inflammation and activate healing process which involves activation of the T Helper type 2 cell signalling (KE4), during which anti-inflammatory and pro-repair/fibrotic molecules are secreted. Once the healing process is initiated, fibroblast proliferation and myofibroblast differentiation is induced (KE5) leading to synthesis and deposition of extracellular matrix or collagen (KE6). Exaggerated collagen deposition leads to alveolar septa thickening, decrease in total lung volume and lung fibrosis (Adverse Outcome).
Lung fibrosis can be induced by many substances, microorganisms or by over expression of specific inflammatory mediators such as cytokines and chemokines. This AOP is also applicable to materials such as nanomaterials that induce an inflammatory response as well as possess unique properties that allow for significant chronicity of the response, which takes place deep within the lung, beyond the airways and within the alveoli. Lung fibrosis occurs in humans and the key biological events involved are the same as the ones observed in experimental rodent models. Thus, this AOP provides a detailed mechanistic account of the process of lung fibrosis across species.