© 2003 American Thoracic Society
Plunging into the Chaos of the Cytokine/Chemokine Cocktail in Pulmonary FibrosisHow Many and How Important Are They?Instituto Nacional de Enfermedades Respiratorias México DF, México Pulmonary fibrosis is the final result of a variety of lung injuries of known (e.g., asbestosis) or unknown etiology (e.g., idiopathic pulmonary fibrosis). Excessive accumulation of extracellular matrix implies a dysregulated tissue repair process probably as a consequence of an unsynchronized cross-talk between resident cells (epithelial cells and fibroblasts as supposedly occurs in idiopathic pulmonary fibrosis) or between them and inflammatory cells, as is found in most interstitial lung diseases that can evolve to fibrosis (1). Ultimately, the temporal and spatial sequence of the fibrotic response seems to be mediated by an as yet unclear repertoire of chemokines, cytokines, and growth factors. The large number of mediators whose expression is increased in experimental and human fibrosis, however, as well as their redundancy and pleiotropic effects makes it difficult to distinguish the factor(s) that play a pivotal role in fibrogenesis. The key question is whether an upregulated mediator is a cause or an effect. Is it the result of lung damage or is it implicated in the development of the fibrotic pathway? This dilemma has been approached in vivo using two strategies: first by the use of transgenic and knock-out mice, and second by inducing transient overexpression of an individual factor introduced in the lung epithelium (2). Targeted gene disruption is a powerful tool for generating models of human disease. The resulting gene defect, however, is present throughout the lifetime of the animal (including development) and therefore yields a situation that may not resemble what occurs in complex human diseases. More likely, these models are represented in humans by rare syndromes that can be traced to altered functions of specific genes. Likewise, until the advent of the doxycycline-inducible reverse tetracycline transactivator, the standard transgenic approaches were limited by the same problem (3). Theoretically, with this externally regulatable system it is possible to overexpress transgenes in a temporally coordinated fashion in vivo. Nevertheless, this system is often affected by a baseline leak of the transgene expression, and additional systems complicating the approach, such as the tetracycline-controlled transcriptional silencer has been proposed (4). In contrast, the use of a recombinant replication–deficient adenovirus vector to transfer human genes to rodent lung, allows a transient but prolonged (1–2 weeks) overexpression of the protein (5, 6). Notably, adenovirus vector has striking trophism for lung epithelium, thus allowing a highly efficient gene transport into the epithelial cells from the respiratory bronchioles and adjacent alveoli. Using this approach, Bonniaud and colleagues (7) describe, in this issue of the Journal (770–778), the effects of the transient overexpression of connective tissue growth factor into rat lungs. This factor is one of the molecules mediating downstream gene transcriptional activity of transforming growth factor-ß, a pivotal profibrotic mediator, and it has recently received much attention as a possible determinant of progressive scarring (8, 9). In this context, connective tissue growth factor is usually found to be upregulated in numerous fibrotic disorders, including those in the lung (10–12). Moreover, it is highly expressed in idiopathic pulmonary fibrosis, particularly in proliferating type-2 alveolar epithelial cells and fibroblasts suggesting that these cells play a pivotal role in lung fibrogenesis (13). Surprisingly, however, Bonniaud and coworkers have found that overexpression of connective tissue growth factor caused only a moderate and short-lived fibrotic reaction in the rat lungs, measured morphologically and biochemically. Strong positive signal for human connective tissue growth factor was obtained in the lungs at 3 and 7 days after intratracheal injection, whereas a patchy fibrotic reaction was observed at 14 days at which time the transgene was no longer expressed. It is important to emphasize that the transient upregulation of the active transforming growth factor-ß under the same conditions provokes an extensive, persistent, and even progressive fibrosis in the lungs (6). The reason(s) for the enormous difference in the fibrotic response to these two factors is not clear, but strongly suggests that there are connective tissue growth factor–dependent and –independent pathways in the fibrogenic effects of transforming growth factor-ß. In this context, one of the most potent profibrotic effects of the transforming growth factor-ß is related to the balance of matrix metalloproteinases with metalloproteinase tissue inhibitors, which is crucial in the remodeling of extracellular matrix. This mediator reduces collagenolytic activity by inducing a strong decrease of collagenase-1 with a concomitant marked increase of tissue inhibitors of metalloproteinases-1 (14). In the experimental model presented by Bonniaud and coworkers, the connective tissue growth factor provoked only an ephemeral increase of this inhibitor, whereas the transforming growth factor-ß caused a stronger and persistent elevation. Because appropriate tissue repair depends on a balance between lung synthesis, deposition, and degradation of matrix components, upregulation of tissue inhibitors of metalloproteinases should have an important effect on extracellular matrix accumulation. In support of this concept, excessive inhibition of matrix metalloproteinases may create a strong nondegrading microenvironment promoting excessive deposition of fibrous tissue in the lung parenchyma, as has been suggested in experimental and human lung fibrosis (15–17). An additional important consideration arises from the findings of Bonniaud and coworkers: is lung fibrosis a reversible event? And if so, what is the moment in its progression when this pathologic process is still reversible? At 14 days after connective tissue growth factor instillation, myofibroblast expansion and excessive lung collagen and fibronectin accumulation was observed. All of these alterations, however, had essentially resolved at 28 days. Although it is theoretically possible that some animals studied at 28 days had developed, at earlier time points, less severe initial lesions from which they recovered before being killed, it is more likely that, in some way, fibrotic lesions were reversible. If this is the case, what are the mechanisms that mediate this regression? Is the extent of the initial profibrotic lesions or the expression of some antifibrotic cytokine key elements? Because available therapies for many chronic fibrotic lung disorders are ineffective, novel approaches to decrease the scarring response are urgently needed. Studies delineating molecular pathways that involve extracellular matrix regulation should focus not only on aberrant accumulation but also on possible regression mechanisms. This should open new avenues for therapy. FOOTNOTES Conflict of Interest Statement: M.S. has no declared conflict of interest. REFERENCES
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