IPF Pathogenesis: The Disease Model

The traditional model of IPF pathogenesis focused on chronic inflammation as a key mediator of disease.6 Early bronchoscopy studies suggested patients with IPF had increased neutrophilic inflammation in bronchoalveolar lavage fluid7; however, several lines of evidence now suggest that this finding may have more likely been a correlate of, rather than cause of, disease in patients with IPF. Careful histopathologic analysis has demonstrated that in patients who are not experiencing acute exacerbations, marked alveolar inflammatory cell infiltration is unusual in IPF.8 In addition to other human studies and animal models, the recent controlled, randomized trial comparing traditional “anti-inflammatory” therapy with prednisone and azathioprine suggested no benefit (and potentially harm) of this treatment regimen in patients with IPF.9 Based on these data, it appears that excessive and/or chronic inflammation is not the primary mediator of fibrotic remodeling in IPF lungs.

An alternative hypothesis was summarized by Selman and colleagues in 2001, which focused on alveolar epithelial cell injury and repair mechanisms, likening IPF to an inappropriate or over-exuberant wound-healing response.10 The subsequent description of mutations in surfactant proteins111213 (produced exclusively by lung epithelial cells) in familial cases of IPF further highlighted a key role for alveolar epithelial cell (AEC) dysfunction in IPF pathogenesis.

Content contributed by:
Jonathan A. Kropski, MD
Vanderbilt University