© 2003 American Thoracic Society
To Clot or Not to Clot, That Is the Question in Pulmonary FibrosisDivision of Pulmonary and Critical Care Medicine Departments of Medicine, and Pathology and Laboratory Medicine David Geffen School of Medicine at UCLA Los Angeles, California Over the last several decades, knowledge has been gained regarding mechanisms of lung injury and repair. Normal repair in response to injury results in rapid tissue restoration. Although the process is complex, it is dependent on overlapping sequential interaction of events related to coagulation, inflammation, granulation tissue formation, and re-epithelialization/reendothelialization in the absence of overexuberant deposition of extracellular matrix or fibrosis (1, 2). In contrast, in interstitial lung disorders, in which fibrosis is a hallmark, the reparative process may be dysfunctional at multiple levels (3–6). The balance between coagulation and fibrinolysis during normal repair is critical. This balance initially tips in favor of fibrin deposition through two mechanisms: enhanced activation of coagulation and concomitant inhibition of the fibrinolytic pathways. The deposition of fibrin establishes provisional matrix, microenvironment for the infiltration of mesenchymal-derived cells and development of more mature extracellular matrix. Therefore, aberrant fibrin deposition and inhibition of its degradation results in a microenvironment favorable for fibrosis. In this issue of AJRCCM (pp. 1687–1694), Fujimoto and colleagues (7) examined bronchoalveolar lavage fluid from 82 patients with interstitial lung disorders. Two inhibitors of fibrinolysis, thrombin-activatable fibrinolysis inhibitor and protein C inhibitor were markedly elevated and inversely correlated with fibrinolytic activity in the bronchoalveolar fluid from patients with interstitial lung disorders. This study is important, as these findings add two additional factors to the list of inhibitors (namely, type 1 plasminogen activator inhibitor [8–10]) of fibrinolysis that may play an important role in promoting fibrosis associated with interstitial lung disorders. The study consisted of 82 patients with interstitial lung disorders, subcategorized into idiopathic pulmonary fibrosis, eosinophilic pneumonia, sarcoidosis, hypersensitivity pneumonitis, cryptogenic organizing pneumonia, and collagen vascular disease–associated interstitial lung disease (7). Control subjects were eight healthy volunteers. They found that total protein, biomarkers of coagulation pathway activation (i.e., thrombin–antithrombin), and procollagens were significantly elevated in all patients with interstitial lung disorders, supporting the notion that active coagulation correlates with fibrogenesis in these diseases (7). Because the persistence of fibrin in the lung is related to the magnitude of activation of coagulation and inhibition of fibrinolytic pathways, Fujimoto and colleagues (7) assessed the bronchoalveolar fluid for presence of inhibitors of fibrinolysis: thrombin-activatable fibrinolysis inhibitor, protein C inhibitor, and type 1 plasminogen activator inhibitor. The levels of these inhibitors of fibrinolysis were directly correlated to biomarkers of activation of coagulation and inhibition of the fibrinolytic pathways and evidence of fibrogenesis in the bronchoalveolar fluid of patients with interstitial lung disorders. Whereas thrombin-activatable fibrinolysis inhibitor, protein C inhibitor, and type 1 plasminogen activator inhibitor tended to be elevated in all patients with interstitial lung disorders, some values did not reach statistical significance due to the number of patients in each subcategory. Moreover, not all three of these inhibitors of fibrinolysis were found to be uniformly elevated in all subcategories of disease. With regard to this latter issue, both thrombin-activatable fibrinolysis inhibitor and protein C inhibitor were elevated in all interstitial lung disorders, whereas type 1 plasminogen activator inhibitor was not significantly elevated in patients with idiopathic pulmonary fibrosis. These findings suggest that a common theme for interstitial lung disorders is the presence of activation of coagulation and inhibition of fibrinolysis pathways, although the factors that promote these events may differ depending on the specific disorder. On the basis of these findings, Fujimoto and associates (7) raised the appropriate question as to whether thrombin-activatable fibrinolysis inhibitor was simply elevated in the plasma and extravasated into the alveolar airspace or whether it was locally produced in the lung in patients with these disorders. To answer this question, they first compared the levels of thrombin-activatable fibrinolysis inhibitor in bronchoalveolar fluid and in plasma. Although all patients with interstitial lung disorders had elevated levels of thrombin-activatable fibrinolysis inhibitor in plasma, the levels in bronchoalveolar fluid were markedly greater than in plasma suggesting local production of the inhibitor in the lung. Moreover, they demonstrated that alveolar macrophages, airway epithelial cells, and a bronchoalveolar carcinoma cell line all constitutively expressed thrombin-activatable fibrinolysis inhibitor messenger RNA, suggesting that cells from the lung are capable of expressing this factor. To demonstrate the important interplay of activation of coagulation and inhibition of the fibrinolytic pathways with inflammation, Fujimoto and colleagues (7) demonstrated that levels of thrombin-activatable fibrinolysis inhibitor, protein C inhibitor, and type 1 plasminogen activator inhibitor were directly correlated with the proinflammatory CC chemokine, monocyte chemoattractant protein-1. This chemokine is known to play a significant role in mediating recruitment of mononuclear phagocytes in the lung during bleomycin-induced pulmonary fibrosis (11, 12) and has been found to be markedly elevated in bronchoalveolar fluid of patients with sarcoidosis and idiopathic pulmonary fibrosis (13). Moreover, thrombin and fibrin can directly induce the expression of this chemokine (14). These findings support the overlapping nature of coagulation, inhibition of fibrinolysis, inflammation, and promotion of pulmonary fibrosis in interstitial lung disorders. Although Fujimoto and associates (7) demonstrated the presence of inhibitors of fibrinolysis in the bronchoalveolar fluid of patients with interstitial lung disorders, a question remains as to what, if any, is the specific and absolute contribution of each of the inhibitors to overall inhibition of fibrinolysis in interstitial lung disorders. In an attempt to answer this question, the investigators used a strategy to estimate fibrinolytic activity (the ratio of plasminogen activator activity to thrombin–antithrombin), and compared each of the fibrinolysis inhibitors. When combined (see Figure 4E of reference 7), however, thrombin-activatable fibrinolysis inhibitor, protein C inhibitor, and type 1 plasminogen activator inhibitor account for approximately 200% inhibition of fibrinolysis. Does this mean we have 200% inhibition of fibrinolysis, or do these findings suggest that the inhibitors may be interactive for their optimal expression? Indeed, protein C inhibitor may have a role in the regulation of the expression of thrombin-activatable fibrinolysis inhibitor (15). Nevertheless, the findings of this study support the notion that inhibitors of the fibrinolytic pathway in the lung play an important role in promoting a microenvironment that is favorable to promote fibrosis. Where do we go from here? The findings of this study and others support the importance of activation of coagulation, and inhibition of the fibrinolytic pathways is interconnected with inflammation and fibrosis in interstitial lung disorders. Preclinical studies have demonstrated that either inhibiting coagulation or augmenting the fibrinolytic pathways directly impacts on reducing pulmonary fibrosis (16). In an era of increasing concern for the efficacy of conventional immunotherapy in interstitial lung disorder–associated fibrosis, perhaps there has never been a better time to contemplate novel interventions that specifically target aberrant coagulation and anti-fibrinolysis in the lung to attenuate pulmonary fibrosis in these disorders. REFERENCES
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