What differentiates normal lung repair and fibrosis? Inflammation, resolution of repair, and fibrosis.

There has been ongoing controversy related to what differentiates normal lung repair and fibrosis. For example, the current prevailing concept has been that idiopathic forms of pulmonary fibrosis are due only to epithelial injury in response to some unknown cause that results in persistent evolving fibrosis without preceding inflammation. This concept would suggest that the lung responds to injury in a different manner than other organs, such as the liver, kidney, and heart. However, that would seem to contradict known established pathological concepts. To address this controversy, concepts were presented as follows: (1) loss of basement membrane integrity is critical in determining the "point of no return," and contributes to the inability to reestablish normal lung architecture with promotion of fibrosis; (2) loss of epithelial cells, endothelial cells, and basement membrane integrity in usual interstitial pneumonia associated with idiopathic pulmonary fibrosis leads to destroyed lung architecture and perpetual fibrosis; (3) transforming growth factor-beta is necessary, but not entirely sufficient, to promote permanent fibrosis; (4) persistent injury/antigen/irritant is critical for the propagation of fibrosis; (5) idiopathic pulmonary fibrosis is an example of a process related to the persistence of an "antigen(s)," chronic inflammation, and fibrosis; and (6) unique cells are critical cellular players in the regulation of fibrosis. In keeping with the theme of the Aspen Lung Conference, it is hoped that more questions are raised than answered in this presentation, in support of the continued need for research in this area to address these important concepts.