The role of inflammation in the pathogenesis of idiopathic pulmonary fibrosis

Abstract

The role of inflammation in idiopathic pulmonary fibrosis (IPF) is controversial. If inflammation were critical to the disease process, lung pathology would demonstrate an influx of inflammatory cells, and that the disease would respond to immunosuppression. Neither is true. The classic pathology does not display substantial inflammation, and no modulation of the immune system is effective as treatment. Recent data suggest that the pathophysiology of the disease is more a product of fibroblast dysfunction than of dysregulated inflammation. The role of inflammation in disease pathogenesis comes from pathology from atypical patients, biologic samples procured during exacerbations of the disease, and careful examination of biologic specimens from patients with stable disease. We suggest that inflammation is indeed a critical factor in IPF and propose five potential nontraditional mechanisms for the role of inflammation in the pathogenesis of IPF: the direct inflammatory hypothesis, the matrix hypothesis, the growth factor-receptor hypothesis, the plasticity hypothesis, and the vascular hypothesis. To address these, we review the literature exploring the differences in pathology, prognosis, and clinical course, as well as the role of cytokines, growth factors, and other mediators of inflammation, and last, the role of matrix and vascular supply in patients with IPF.

FIG. 1. Inflammation and pulmonary fibrosis

Numerous mediators of inflammation have been implicated in the pathogenesis of IPF. This review proposes five possible hypotheses for the pathogenesis of IPF. (A) The direct inflammation hypothesis suggests that inflammatory cells directly damage the tissues via substances like elastases, as well as cytokines and growth factors, which amplify this process. (B) The matrix hypothesis, in which inflammatory mediators released as a result of a remote injury are trapped in the pulmonary extracellular matrix. This leads to a prolonged and amplified wound-repair mechanism that results in the fibrotic phenotype. (C) The growth factor–receptor hypothesis suggests that some cell types with growth factor receptors proliferate unchecked in this environment, resulting in activation and amplification of the inflammatory cascade. Additionally, these receptors are upregulated in the presence of steroids, suggesting a rationale as to why immunosuppression is not successful in the treatment of IPF. (D) The plasticity hypothesis suggests that numerous cell types can differentiate into other cell types [for example, epithelial cells to mesenchymal cells (EMT), neutrophils and monocytes to macrophages], and this differentiation is a result of complex interactions of inflammatory mediators, growth factors, and other unidentified factors. These activated cells then mediate the fibrotic phenotype. (E) The vascular hypothesis suggests that some initial endothelial injury activates the inflammatory cascade with subsequent antibody deposition and resultant fibrosis. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 2. Direct inflammation hypothesis

Inflammatory cell recruitment is believed to be mediated by chemokines like CCL2, CCL3, and IL8. These facilitate tissue deposition of inflammatory cells with further release of inflammatory mediators such as TGF-β, TNF-α, and others with direct toxic effects (elastase, MMPs, and ECP). These proinflammatory cytokines are linked to profibrotic mediators like CTGF. These complex and incompletely understood interactions eventually result in myofibroblast activation and collagen deposition. Some of these pathways have been delineated, but numerous others still must be further investigated. Data to support this hypothesis largely revolve around the consistent elevation of these inflammatory mediators and cells that are found in pathologic lung biopsy samples, as well as BAL fluid from patients with IPF. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 3. Matrix hypothesis

Repeated and remote lung injury leads to inflammatory cell deposition in the pulmonary extracellular matrix. These cells deposit inflammatory mediators within the matrix where they are entrapped. Dysregulated deposition and clearance of collagen in a repeated wound repair/remodel results in the pathologic findings. Proteoglycans and integrins activate free and matrix-bound TGF-β and CTGF (83). This results in fibroblast (myofibroblasts) activation and subsequent production of collagen type I and type III. Growth factors like IGF-1, TNF-α, FGF, VEGF, IL-1β, PDGF, EGF, and M-CSF (44, 142, 155), as well as other mediators of inflammation, are matrix bound and deposited and result in cell recruitment and activation (110, 148). It is hypothesized that the fibroblastic foci seen in IPF are centers of matrix deposition of these mediators. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 4. Plasticity hypothesis and growth factor–receptor hypothesis

Numerous cells have been shown to undergo phenotypic transformation, and this is well documented. Monocytes can differentiate into macrophages, as can neutrophils. Epithelial cells have been shown to transform into mesenchymal cells, the basis of the epithelial–mesenchymal transformation hypothesis (EMT). We expand on these findings and propose that a CD14⁺ cell may be a progenitor cell that is capable of transforming from a peripheral blood cell to endothelial cells, macrophages, epithelial cells, fibroblasts, fibrocytes, or a combination of these. Additionally, growth factor–receptor expressing cells are resistant to traditional immunosuppression. Glucocorticoids have been shown to upregulate M-CSF receptors on other cells similar to macrophages, like osteoblasts. Once the growth-factor receptors are unregulated, this cell population is sensitized and results in increased cytokine secretion and subsequently activates numerous proinflammatory cascades as well as cross-talks with other inflammatory cell populations. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 5. Vascular hypothesis

Autoantibodies or systemic toxins result in underlying endothelial injury via monocyte recruitment and activation. Once the tissue is injured, antibodies initiate inflammatory cascades and subsequent cellular recruitment. Additionally, this endothelial injury results in a hypercoagulable state, as evidenced by elevated d-dimer and probable microthrombi (86). The antibodies that are seen in patients with UIP (93) may be circulating antinuclear antibodies (122), anti–endothelial cell antibodies (63), or be related to viral processes (94). Subsequent fibroblast activation may be a result of these autoantibodies (66, 92, 156), as well as cellular growth and differentiation via M-CSF–dependent pathways (–98). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).