11th January 2024

Pathophysiology

ILD subtypes all share similar pathophysiological mechanisms, and all primarily affect the same part of the lung: its interstitium. Lung interstitium contains a complex mixture of connective tissue elements, which together create a matrix supporting the respiratory tree and alveoli. It can be subdivided into parenchymal, axial and peripheral compartments. Axial interstitium surrounds primary bronchi and pulmonary arteries and is continuous with interlobular septa. The peripheral compartment contains strong supportive fibres between the visceral pleura and the lung parenchyma. In ILDs, it is the parenchymal interstitium that is mainly affected. It represents the ‘interface’ between alveolar epithelial cells and capillary endothelium, thus supporting the intralobular, gas-exchanging part of the lung.

The two key mechanisms by which the parenchymal interstitium is damaged in ILD are fibrosis and inflammation. Initial insult, be it by an environmental agent, drug, or an autoimmune process, leads to an influx of inflammatory cells; fibroblasts and type II pneumocytes get activated in order to repair the damage. Both processes result in accumulation of extracellular matrix components, which distort the alveolar/capillary interface and impair the gas exchange. As the disease progresses, the architecture of alveolar lumens and bronchi gets distorted as well. Mechanisms at play include alveolar infiltration with proliferating fibroblasts, traction bronchiectasis due to the scarred tissue ‘pulling’ the airways apart, and alveolar haemorrhage due to damaged capillary walls.

It is worth noting that some ILDs are predominantly fibrotic (e.g. IPF), while others are mainly inflammatory (e.g. ILDs in vasculitis), although many demonstrate some combination of the two. Diseases on each end of the spectrum share certain characteristics. For example, fibrotic ILDs tend to have a slower onset, poor response to therapy, and progressive course. In contrast, inflammatory ILDs tend to present acutely or sub-acutely, are mostly treated with immunosuppressive medications, and can be reversible. This distinction is clinically important, as knowing where the disease lies on the fibrosis-inflammation spectrum allows us to predict disease behaviour and response to therapy, even when specific diagnosis is challenging to establish.