A 62-year-old man is evaluated for persistent dry cough and exertional dyspnea that has progressed over the past year. He has had difficulty accomplishing normal daily activities. The patient has no significant medical history and takes no medications. He smoked cigarettes for 10 years and quit 25 years ago. The patient works as an investment banker and does not use alcohol or illicit drugs. Vital signs are normal. Physical examination shows bilateral inspiratory crackles and digital clubbing. CT scan of the chest is shown in the exhibit. Which of the following changes are most likely present in this patient's lung tissue?
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This patient's chronic progressive dyspnea, nonproductive cough, digital clubbing, and inspiratory crackles are concerning for interstitial lung disease. CT reveals peripheral reticular infiltrates (ie, thickened, linear interstitial markings) with subpleural honeycombing (ie, multiple cystic spaces with irregularly thickened walls), which strongly suggests idiopathic pulmonary fibrosis (IPF). IPF is a chronic, fibrosing interstitial pneumonia that is histologically defined by foci of fibroblast proliferation and dense collagen deposition intermixed with unaffected lung (ie, usual interstitial pneumonia pattern).
The pathogenesis of IPF is thought to be driven by repetitive epithelial injury (eg, smoking, acid reflux) followed by disordered repair:
Repetitive lung microinjuries result in the loss of type 1 pneumocytes, which compose 95% of the gas-exchanging alveolar surface area (Choice E).
Type 1 pneumocytes are incapable of replication. Therefore, normal repair requires the proliferation of type 2 pneumocytes, with subsequent differentiation into type 1 pneumocytes to reestablish the alveolar epithelial lining.
In IPF, type 2 pneumocytes undergo reactive hyperplasia but fail to differentiate into type 1 cells because of dysfunctional cell fate pathways (eg, Wnt/transforming growth factor-beta) and abnormalities of the underlying basement membrane (Choices A and C).
Impaired re-epithelialization causes lung fibroblasts to undergo focal proliferation and begin secreting excessive amounts of collagen, leading to interstitial fibrosis (Choice D).
The fibrosis exerts radial traction on the distal airways, leading to dilation of the terminal bronchioles and producing the honeycomb appearance characteristic of IPF.
Educational objective:
Idiopathic pulmonary fibrosis is an interstitial lung disease characterized by chronic progressive dyspnea, nonproductive cough, inspiratory crackles, and subpleural (peripheral) lung honeycombing. In IPF, repetitive microinjury to the alveolar epithelium (eg, smoking, acid reflux) is focally repaired by fibroblast proliferation/collagen deposition instead of normal restoration via type 2 pneumocyte differentiation.