Idiopathic pulmonary fibrosis (IPF), diffuse, patchy irreversible fibrosis of the lung parenchyma, with unknown etiology—a very practical way to describe a deadly disease about which we know very little and can offer very little for therapeutic intervention. The natural history of IPF is unknown, and most conclusions drawn about pathogenesis have evolved from studies of biopsy material from established disease. These “snapshots” of disease activity have been used to implicate inflammation as the major pathogenic mechanism because we see patchy areas of interstitial inflammation, evidence of progressive injury, and tissue remodeling and fibroblastic foci, with dense deposits of collagen and honeycomb changes, now collectively termed “usual interstitial pneumonia” (1–3). However, these terms describe the morphology there now, not how it developed. It is likened to asking someone who had been held incommunicado for the past 6 months to decipher what happened to the World Trade Towers using only a “snapshot” of Ground Zero as it is today. This is hardly a case for much conviction in current conclusions about the pathogenesis of IPF. Animal models of pulmonary fibrosis have been studied, but they are, by default, of known etiology, and the only real similarity is that they display fibrogenesis.

Nonetheless, for the past 30 odd years, we have approached this disorder by assuming that it is a chronic inflammatory disease, and therapy must therefore attack the inflammatory pathways that propagate the progressive nature of the disorder (3). Alas, this has taken us nowhere, with the most potent of antiinflammatory drugs yielding little or no effect in IPF (2, 4) (to the point that some clinicians commonly use response and/or nonresponse to corticosteroid treatment as a differential diagnosis from other lung inflammatory fibrotic diseases). How, then, can we be so sure of the involvement of inflammation in the pathogenesis of the disease? In fact, when one examines the accumulated human evidence in detail (2) and looks to other experimental data and models of fibrogenesis for clues to pathogenesis, it is just as easy to conclude that the inflammation we see in biopsy material is paraphenomena, associated with a more direct tissue-based defect in cell injury, communication, and repair (5, 6).

Instead of inflammation driving the fibrogenic process with chronicity an aspect of repeated episodes of injury, I would argue that after an initial insult or injury, the normal physiologic response of inflammation leads to matrix stimulation with proliferation and altered phenotype of mesenchymal cells (fibrogenesis) to stop the injury and provide temporary repair. This is usually followed by matrix mobilization (fibrolysis) and apoptosis of repair cells, both mesenchymal and inflammatory, and return to normal organ function. In the case of IPF, this normal process is diverted, with retention of altered mesenchymal cell phenotype (fibroblasts and myofibroblasts) through avoidance of apoptosis, with continued matrix production and reduced matrix mobilization. In addition, the altered stromal cell population and activated epithelium release a series of profibrogenic factors, such as transforming growth factor-β and platelet-derived growth factor, which interact with the deposited matrix at the site of abnormal repair (7), thus creating a new microenvironment in patchy areas of the lung. Other areas remain in normal structure and environment.

The ability of matrix to sequester many growth and differentiation factors to create a “fibrogenic” microenvironment is well established (7, 8). Many of these factors act on inflammatory cells in normal passage through the tissue modulating susceptibility to normal apoptosis, resulting in accumulation of these cells and apparent “inflammation.” Thus, “inflammation” is a result of a new microenvironment caused by abnormal interaction between mesenchyme and epithelium (9, 10). Such an interaction is mandatory in normal growth and development of the lung (11), and it is not unexpected for the body to recapitulate the process when injury and repair are initiated in the adult. These data fit well with experimental fibrosis models such as the αvβ6 integrin knockout mouse, which cannot activate transforming growth factor-β from the latent form and which develops marked inflammation on exposure to bleomycin but fails to develop fibrosis (12). It also fits well with the concept of genetic factors influencing the prevalence of IPF, as altered microenvironments can occur through permanent or long-term alterations, possibly genetic, to the structural elements in limited areas of the lung. This can cause behavioral shifts (phenotype) in fibroblasts and epithelial cells, leading to altered matrix metabolism and fibrogenesis. Such hyperactive fibroblasts have been shown in numerous studies on cell lines established from human and animal fibrotic tissue (13) and from Rel-B knockout mice with fibroblasts displaying sustained and persistent production of a wide array of inflammatory chemokines (14).

The concept of the microenvironment driving the “inflammatory” state also fits with our own data showing that overexpression of active transforming growth factor-β1 in lung epithelial cells causes progressive fibrosis without apparent inflammation (15). Only after fibrosis has been established for some time is there the accumulation of mast cells, likely through expression of transmembrane stem cell factor on myofibroblasts in the fibrotic tissue (16). The concept of fibroblasts and epithelial cells actively creating an “inflammatory” microenvironment and regulating a switch from acute resolving to chronic persistent fibrotic tissue has been recently suggested for other disorders, including rheumatoid arthritis (8). The role of the matrix in sequestering chemokines, cytokines, and growth factors and thereby defining fibrogenic conditions has been documented in liver fibrosis, a process with similar pathogenic mechanisms and one that resolves through activation of fibrolytic systems and mobilization of deposited matrix (7, 8). Thus, altered structural cells and matrix are readily capable of supplying growth factors to promote the fibrogenic process in an extended manner, independent of any contribution from inflammatory cells. In essence, the “inflammation” arises from conditions defined by the tissue and appears subsequent to the tissue changing the microenvironment. This could explain the tissue-limited and patchy nature of IPF and the importance of ongoing epithelial damage (17) and suggests that we need to understand the nature of the microenvironment and how to change it to attack the fibrotic disorder and initiate a fibrolytic environment to attain resolution. Perhaps, instead of inhibiting inflammation, we should be trying to activate some inflammatory processes, at least those that target matrix mobilization (18).

Jack Gauldie

Department of Pathology and

Molecular Medicine

McMaster University

Hamilton, Ontario, Canada

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