This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cook, D. N. Articles by Schwartz, D. A. Search for Related Content PubMed PubMed Citation Articles by Cook, D. N. Articles by Schwartz, D. A.

A Matrix for New Ideas in Pulmonary Fibrosis

Pulmonary and Critical Care Division, Department of Medicine, and the Department of Veterans Affairs Medical Center and Duke University Medical Center, Durham, North Carolina

Address correspondence to: David A. Schwartz, M.D., M.P.H., Pulmonary and Critical Care Medicine, Duke University Medical Center, Research Drive, Room 275 MSRB, DUMC Box 2629, Durham, NC 27710. E-mail: david.schwartz{at}duke.edu

Abbreviations: extracellular matrix, ECM • expressed sequence tags, EST • hyaluronic acid, HA • matrix metalloproteinase, MMP • transforming growth factor, TGF • tissue inhibitor of metalloproteinase, TIMP

	Introduction

Top Introduction References

 
Pulmonary fibrosis is a progressive and ultimately fatal condition, characterized pathologically by mesenchymal cell proliferation in the lung, expansion of the extracellular matrix (ECM), and extensive remodeling of the lung parenchyma. Although the pathogenesis of this disease is complex and poorly understood, growth factors, cytokines, chemokines, and regulators of apoptosis have all been implicated in its progression. Pulmonary fibrosis has been traditionally viewed as a consequence of inflammation, but this interpretation has been questioned in recent years because clinical measures of inflammation do not correlate well with disease progression and because anti-inflammatory drugs do not significantly affect clinical outcome. For these reasons, recent attention has focused on the ECM and molecules that normally regulate its homeostasis.

Among the molecules thought to regulate matrix deposition, transforming growth factor (TGF)-ß1 is probably the best-studied. This fibrogenic growth factor is upregulated in lung parenchyma from patients with idiopathic pulmonary fibrosis (1), it increases the production of collagen and other extracellular matrix components (2–4), and it regulates the expression of other genes associated with ECM degradation and proteolysis. Moreover, adenoviral delivery of active TGF-ß1 to rat lung results in architectural changes similar to those seen in pulmonary fibrosis (5). Other studies have revealed that overexpression of granulocyte macrophage–colony stimulating factor (2), tumor necrosis factor- (3), and interleukin-13 (4) also result in myofibroblast proliferation and ECM deposition. Interestingly, a common feature among these latter studies is the upregulation of TGF-ß1 expression in the lung, further supporting the hypothesis that this cytokine plays an important role in pulmonary fibrosis.

Additional evidence for the importance of TGF-ß1 in pulmonary fibrosis is provided by the observation that TGF-ß1 may play a role in susceptibility to fibrogenic agents in mice. For example, expression of TGF-ß1 in the lung is relatively low in inbred mice that fail to develop fibroproliferative lesions following inhalation of asbestos (6). In this issue, Kolb and coworkers explore the biologic relevance of this observation by expressing high levels of TGF-ß1 in the lungs of both fibrosis-prone and fibrosis-resistant mouse strains (7). Their finding that the fibrosis-resistant Balb/c mice have significantly less fibrosis—even when expressing higher levels of TGF-ß1 than the sensitive C57BL/6 mice—demonstrates that at least in this model, differences in TGF-ß1 expression alone cannot account for differences in susceptibility to fibrosis. The authors further demonstrate that the relative lack of fibrosis in Balb/c mice receiving active TGF-ß1–encoded adenovirus is not due to their inability to respond to this cytokine, because primary fibroblasts derived from these mice do not differ significantly from their C57BL/6-derived counterparts in their ability to synthesize collagen following stimulation with TGF-ß1 (7). Based on this observation, the authors conclude that the difference in susceptibility to fibrosis between these two mouse strains results from genetic differences in one or more unidentified genes that function downstream of TGF-ß1. Clearly, the identification and characterization of these genes would be a major contribution to our understanding of pulmonary fibrosis.

It is becoming increasingly clear that the maintenance of ECM is a dynamic process in which the synthesis of proteins such as fibrillar collagens, fibronectin, and proteoglycans is normally balanced by similar rates of proteolysis. Protein turnover in the ECM is mediated in large part by a class of proteases known as matrix metalloproteinases (MMPs) (8). Recently, one of these MMPs, matrilysin (MMP-7), was shown to be expressed at much higher levels in both human fibrotic lung and in bleomycin-induced pulmonary fibrosis in mice (9). Control of MMPs is complex and occurs at many stages, including transcription, post-transcriptional RNA processing, and cellular localization. The enzymatic activities of MMPs are further regulated by a family of tissue inhibitors of metalloproteinases (TIMPs), of which four members are currently known. Interestingly, Kolb and colleagues find that although TIMP-1 expression is upregulated by TGF-ß1 in both fibrosis-sensitive C57BL/6 and fibrosis-resistant Balb/c mice, the extent of induction is less in Balb/c mice (7). Based on this observation, the authors suggest that differences in the fibrotic response in these two strains of mice might result not from differences in the rate of matrix deposition, but from differences in its degradation. This interpretation is in line with recent findings with mice lacking the hyaluronic acid (HA) receptor, CD44. Compared with wild-type controls, CD44-deficient mice have increased inflammation and increased HA following bleomycin treatment, despite having lower levels of activated TGF-ß1 (10). Thus, the regulation of ECM deposition is complex and cannot be explained by levels of TGF-ß1 alone.

One approach to addressing the complexity of fibrosis is to conduct large-scale gene expression studies such as microarray analyses. This approach has yielded useful information in many experimental systems, and suggests that ECM structural and regulatory proteins such as MMP-7, tenascin C, osteopontin, tropoelastin, and fibronectin might have key roles in pulmonary fibrosis (9, 11). In addition to these known genes, most microarrays also include expressed sequence tags (EST), from which novel genes participating in pulmonary fibrosis can be identified. In these types of experiments, it is critical to discriminate between genes (or ESTs) whose expression is increased only during end-stage fibrosis and genes whose products have a functional role in the initiation or progression of fibrosis—not always a straightforward task. For example, the current work of Kolb and coworkers demonstrates that although TGF-ß1 is more highly expressed in C57BL/6 mice than in Balb/c mice, this difference is unlikely to account for the difference in susceptibility to fibrosis between the two strains (7). This finding does not rule out the possibility that TGF-ß1 levels are important to disease outcome in clinical settings or in other experimental models of fibrosis, but it underscores the need for studies that complement expression analyses. Clearly, a combination of experimental approaches that include large-scale expression studies, mapping of chromosomal loci, focused biologic studies, and the generation of novel gene-targeted mice will be required to gain a thorough understanding of this debilitating and fatal disease. Such an understanding should eventually lead to improved understanding of disease pathogenesis and to novel molecular targets for therapeutic intervention.

View larger version (48K): [in this window] [in a new window]   Figure 1. Schematic diagram of ECM homeostasis in the lung. Factors acting to increase matrix deposition in the lung include the production of ECM components, and increased levels of TGFß and TIMP family members. Factors that function to degrade the ECM include CD44-expressing cells and the family of MMPs. Homeostasis requires a balance between these two types of factors, whereas pulmonary fibrosis results from a disproportionately high activity of one or more pro-fibrotic factors.

	Acknowledgments

Received in original form May 31, 2002

	References

Top Introduction References

 

1. Broekelmann, T. J., A. H. Limper, T. V. Colby, and J. A. McDonald. 1991. Transforming growth factor ß1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis. Proc. Natl. Acad. Sci. USA 88:6642–6646.[Abstract/Free Full Text]
2. Xing, Z., G. M. Tremblay, P. J. Sime, and J. Gauldie. 1997. Overexpression of granulocyte-macrophage colony-stimulating factor induces pulmonary granulation tissue formation and fibrosis by induction of transforming growth factor-beta 1 and myofibroblast accumulation. Am. J. Pathol. 150:5 9–66.
3. Sime, P. J., R. A. Marr, D. Gauldie, Z. Xing, B. R. Hewlett, F. L. Graham, and J. Gauldie. 1998. Transfer of tumor necrosis factor-alpha to rat lung induces severe pulmonary inflammation and patchy interstitial fibrogenesis with induction of transforming growth factor-beta1 and myofibroblasts. Am. J. Pathol. 153:825–832.[Abstract/Free Full Text]
4. Lee, C. G., R. J. Homer, Z. Zhu, S. Lanone, X. Wang, V. Koteliansky, J. M. Shipley, P. Gotwals, P. Noble, Q. Chen, R. M. Senior, and J. A. Elias. 2001. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1). J. Exp. Med. 194:809–821.[Abstract/Free Full Text]
5. Sime, P. J., Z. Xing, F. L. Graham, K. G. Csaky, and J. Gauldie. 1997. Adenovector-mediated gene transfer of active transforming growth factor-ß1 induces prolonged severe fibrosis in rat lung. J. Clin. Invest. 100:768–776.[Medline]
6. Brass, D. M., G. H. Hoyle, H. G. Poovey, J.-Y. Liu, and A. R. Brody. 1999. Reduced tumor necrosis factor-alpha and transforming growth factor-beta1 expression in the lungs of inbred mice that fail to develop fibroproliferative lesions consequent to asbestos exposure. Am. J. Pathol. 154:853–862.[Abstract/Free Full Text]
7. Kolb, M., P. Bonniaud, T. Galt, P. J. Sime, M. M. Kelly, P. J. Margetts, and J. Gauldic. 2002. Differences in the fibrogenic response after transfer of active transforming growth factor-ß1 gene to lungs of "fibrosis-prone" and "fibrosis-resistant" mouse strains. Am. J. Respir. Cell Mol. Biol. 27:141–150.[Abstract/Free Full Text]
8. Sternlicht, M. D., and Z. Werb. 2001. How matrix metalloproteinases regulate cell behavior. Annu. Rev. Cell Dev. Biol. 17:463–516.[Medline]
9. Zuo, F., N. Kaminski, E. Eugui, J. Allard, Z. Yakhini, A. Ben-Dor, L. Lollini, D. Morris, Y. Kim, B. DeLustro, D. Sheppard, A. Pardo, M. Selman, and R. A. Heller. 2002. Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. Proc. Natl. Acad. Sci. USA 99:6292–6297.[Abstract/Free Full Text]
10. Teder, P., R. W. Vandivier, D. Jiang, J. Liang, L. Cohn, E. Pure, P. M. Henson, and P. W. Noble. 2002. Resolution of lung inflammation by CD44. Science 296:155–158.[Abstract/Free Full Text]
11. Kaminski, N., F. Zuo, G. Cojocaro, Z. Yakhini, A. Ben-Dor, D. Morris, D. Sheppard, A. Pardo, M. Selman, and R. A. Heller. 2002. Use of oligonucleotide microarrays to analyze gene expression patterns in pulmonary fibrosis reveals distinct patterns of gene expression in mice and humans. Chest 121(Suppl. 3):31S–32S.[Free Full Text]

This article has been cited by other articles:

				W. D. Hardie, T. D. Le Cras, K. Jiang, J. W. Tichelaar, M. Azhar, and T. R. Korfhagen Conditional expression of transforming growth factor-{alpha} in adult mouse lung causes pulmonary fibrosis Am J Physiol Lung Cell Mol Physiol, April 1, 2004; 286(4): L741 - L749. [Abstract] [Full Text] [PDF]

				L Atzori, F Chua, S E Dunsmore, D Willis, M Barbarisi, R J McAnulty, and G J Laurent Attenuation of bleomycin induced pulmonary fibrosis in mice using the heme oxygenase inhibitor Zn-deuteroporphyrin IX-2,4-bisethylene glycol Thorax, March 1, 2004; 59(3): 217 - 223. [Abstract] [Full Text] [PDF]

				P. Bonniaud, P. J. Margetts, M. Kolb, T. Haberberger, M. Kelly, J. Robertson, and J. Gauldie Adenoviral Gene Transfer of Connective Tissue Growth Factor in the Lung Induces Transient Fibrosis Am. J. Respir. Crit. Care Med., October 1, 2003; 168(7): 770 - 778. [Abstract] [Full Text] [PDF]

				T. A. Lyerla, M. E. Rusiniak, M. Borchers, G. Jahreis, J. Tan, P. Ohtake, E. K. Novak, and R. T. Swank Aberrant lung structure, composition, and function in a murine model of Hermansky-Pudlak syndrome Am J Physiol Lung Cell Mol Physiol, September 1, 2003; 285(3): L643 - L653. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cook, D. N. Articles by Schwartz, D. A. Search for Related Content PubMed PubMed Citation Articles by Cook, D. N. Articles by Schwartz, D. A.