Pulmonary fibrosis has multiple possible causes, and in a substantial proportion of cases the precise initiating cause cannot be identified. The term therefore covers both known-cause fibrotic lung diseases and idiopathic disorders. The fundamental process involves repeated or abnormal injury to the alveolar epithelium and an altered repair response in which fibroblasts and other cells produce excessive extracellular matrix. Instead of restoring normal lung architecture, the repair process becomes dysregulated and progressively remodels the interstitium. The trigger can be autoimmune inflammation, inhaled environmental material, occupational exposure, medication toxicity, radiation, genetic susceptibility or other mechanisms.
Idiopathic pulmonary fibrosis, or IPF, is the best-known idiopathic form. Its cause is not established, and it is thought to result from complex interactions among ageing-related epithelial vulnerability, genetic susceptibility and environmental factors. Repeated microscopic injury to alveolar epithelial cells may lead to abnormal wound-healing responses and activation of fibroblasts, producing characteristic fibrotic lesions. Cigarette smoking is associated with increased risk, but smoking does not provide a complete explanation for IPF. Age is an important epidemiological factor, and certain genetic variants affecting surfactant biology, telomere maintenance and other cellular pathways can increase susceptibility in some families or individuals.
Autoimmune and connective-tissue diseases can cause pulmonary fibrosis through immune-mediated lung injury and abnormal repair. Systemic sclerosis is strongly associated with interstitial lung disease, while rheumatoid arthritis, polymyositis or dermatomyositis, Sjögren syndrome and other connective-tissue disorders can also involve the lungs. The precise mechanisms differ between diseases but may include persistent immune activation, epithelial injury and fibroblast stimulation. In some patients, lung disease may be detected before the systemic autoimmune diagnosis is fully established, making careful assessment for subtle joint, skin, muscle, vascular or other systemic features important.
Hypersensitivity pneumonitis is an immune-mediated lung disorder caused by repeated inhalation of sensitising organic particles. Sources can include mould, bird proteins, agricultural materials and other biological antigens. Continued exposure can lead from inflammation to irreversible fibrosis in susceptible individuals. Occupational and environmental histories are therefore particularly important. Pneumoconioses such as silicosis and other dust-related diseases can also cause fibrotic lung injury after prolonged inhalation of mineral particles. Asbestos exposure can cause pleural disease and asbestosis, a form of interstitial fibrosis involving the lung parenchyma.
Medications and medical treatments can produce pulmonary fibrosis in susceptible people. Drugs associated with interstitial lung toxicity include certain chemotherapy agents, amiodarone and several other medicines, with the specific risk depending on the drug, dose, duration and individual susceptibility. Radiation therapy involving the chest can cause radiation pneumonitis followed by radiation fibrosis in some patients. Drug-induced or treatment-associated fibrosis requires careful chronological assessment because the presence of a medication exposure does not automatically establish causality. Clinicians must balance the respiratory problem against the importance of the medicine and should not stop essential treatment without appropriate medical advice.
Genetic factors can influence susceptibility to pulmonary fibrosis. Familial pulmonary fibrosis can occur when multiple relatives develop interstitial lung disease, and variants affecting telomere maintenance, surfactant proteins and other cellular pathways have been identified in some affected families. Short telomeres can impair cellular regenerative capacity and increase vulnerability to repeated epithelial injury. Genetic susceptibility does not mean that a person with a risk variant will necessarily develop fibrosis, because environmental exposures, age and other biological factors also contribute. Genetic testing is therefore considered selectively, particularly where disease occurs unusually early or there is a strong family history.
Certain environmental and occupational exposures can cause or contribute to fibrotic interstitial lung disease. Silica, asbestos, coal dust, metal dust, wood dust, agricultural materials and other inhaled substances have been associated with specific occupational lung disorders. The relationship often depends on cumulative exposure, particle characteristics, workplace controls and individual susceptibility. Detailed questioning about previous employment is important because relevant exposures may have occurred decades before symptoms appear. Fibrosis can also follow severe lung injury or inflammatory disease in some circumstances, although not every episode of pneumonia or lung inflammation results in permanent scarring.
The mechanism shared by many fibrotic lung diseases is therefore not simply “scar tissue appearing spontaneously” but abnormal wound healing after epithelial injury. Persistent injury or immune activation can release signalling molecules that stimulate fibroblast proliferation and differentiation into matrix-producing myofibroblasts. Excess collagen and other extracellular-matrix components accumulate, distort alveolar architecture and progressively reduce lung compliance and gas-transfer capacity.
Identifying the cause matters because some forms are potentially modifiable through exposure avoidance or treatment of an underlying disease, whereas idiopathic forms require specialist assessment and disease-specific management. A diagnosis of pulmonary fibrosis should therefore prompt investigation of occupational and environmental exposures, autoimmune disease, medication history, previous treatments, family history and radiological pattern rather than assuming that all pulmonary fibrosis has the same cause.
