The rationale for their study was based on several previous observations. First, fibrosing alveolitis is a well-recognized morphologic finding in most patients dying with the adult respiratory distress syndrome [2, 3]. Second, increased levels of collagen have been found in the lungs of patients with the adult respiratory distress syndrome who die after the acute phase of lung injury [4, 5]. Third, because the N-terminal peptide of procollagen III is cleaved from the precursor procollagen molecule during collagen synthesis, elevated serum levels of procollagen III have been used as biochemical markers of collagen synthesis in surgical patients after major trauma and orthopedic surgeries [6, 7]. Fourth, increased levels of procollagen III in the serum or bronchoalveolar lavage fluid have been reported in pulmonary sarcoidosis and idiopathic pulmonary fibrosis [8, 9]. Fifth, in one study [10], a correlation was noted between histologic evidence of intra-alveolar fibrosis and elevated levels of procollagen III in bronchoalveolar lavage fluid from five patients with the adult respiratory distress syndrome, but the relation to survival was not examined.

The results of Clark and colleagues' study [1] indicated that the mean procollagen III levels in bronchoalveolar lavage fluid were threefold to fourfold higher at 3 and 7 days after the onset of the adult respiratory distress syndrome in patients who died compared with those who survived. Multivariate analysis of the 117 patients showed that increased procollagen III levels were strongly associated with death even after the statistical analysis controlled for the effect of several other variables that might have been associated with death. These variables included age, the clinical cause of the adult respiratory distress syndrome, the degree of lung injury, and the number of neutrophils and the quantity of protein in the bronchoalveolar lavage fluid. Patients with a procollagen III level greater than 1.75 U/mL in bronchoalveolar lavage fluid on day 7 had a 72% mortality rate compared with a 20% mortality rate in patients with a procollagen III level less than 1.75 U/mL. Also, an elevated procollagen III level was superior to a clinical index of acute lung injury in predicting death.

This study has some limitations. First, considerable overlap exists in the individual procollagen III data points in survivors and nonsurvivors. Second, although a cutoff value for procollagen III in bronchoalveolar lavage fluid (>1.75 U/mL) identified patients with a 2.5 times greater risk for death, this cutoff level (selected after completion of the study) was associated with an approximately 40% false-positive rate for identifying patients who did not survive. Third, no lung biopsy specimens or postmortem studies were done to validate the relation of elevated procollagen III levels in bronchoalveolar lavage fluid to the degree of pulmonary fibrosis. Histologic grading of collagen deposits in the lung is important because procollagen III can be released during degradation of extracellular matrix molecules, and lung destruction occurs in severe cases of the adult respiratory distress syndrome [10, 11]. Despite these shortcomings, the fundamental discovery is important for at least two reasons. First, an elevated procollagen III level in bronchoalveolar lavage fluid has prognostic value for predicting death. Second, the elevated level of procollagen III may reflect additional pulmonary fibrosis, an important component of the respiratory failure in most patients who do not recover from the adult respiratory distress syndrome.

Why is there an association between an index of pulmonary fibrosis and death in patients with the adult respiratory distress syndrome? This question is particularly pertinent because several studies have indicated that death in patients with the adult respiratory distress syndrome is related to factors other than respiratory failure [12-14]. To address this issue, Clark and colleagues analyzed bronchoalveolar lavage fluid from 25 patients on day 7 after onset of the adult respiratory distress syndrome. Fifteen patients recovered, all of whom had resolution of their respiratory failure. In contrast, of the 10 patients who died, 9 had persistent respiratory failure at the time of death, although the cause of death was sepsis or nonpulmonary organ failure in 8 of these 10 patients. Procollagen III levels in bronchoalveolar lavage fluid correlated with the severity of lung dysfunction as measured by the lung injury score. Thus, elevated levels of procollagen III are probably associated with death because this marker of collagen synthesis reflects fibrosing alveolitis and nonresolving respiratory failure, an important characteristic of most patients who die with the adult respiratory distress syndrome.

Other results in Clark and colleagues' study [1] deserve discussion. First, the authors found that sepsis is associated with a higher mortality rate; this finding confirms the importance of stratifying patients according to the clinical disorder associated with the development of the adult respiratory distress syndrome [14]. Second, the lung injury score did not distinguish survivors from nonsurvivors on day 3 but was significantly higher in nonsurvivors than in survivors on day 7. Perhaps most importantly, the combination of a high lung injury score and an elevated procollagen III level in bronchoalveolar lavage fluid on day 7 identified patients with a 73% mortality rate compared with only a 15% mortality rate if neither the procollagen III level nor the lung injury score was elevated. Thus, physiologic indices of acute lung injury are not likely to be of major prognostic value early in the course of acute lung injury. However, these indices may be useful in the subacute phase of acute lung injury, particularly when combined with a biological marker of prognosis. Third, elevated numbers of neutrophils were found in the bronchoalveolar lavage fluid of patients who died. This observation is interesting, particularly because elevated levels of interleukin-8, the major chemotactic factor responsible for recruiting neutrophils into the air spaces of the acutely injured lung, may have some prognostic value for identifying patients who will not survive [15].

Another important finding is that increased levels of procollagen III in bronchoalveolar lavage fluid occurred as early as day 3 after the development of the adult respiratory distress syndrome in patients with a high fatality rate. The quantity of protein in the bronchoalveolar lavage fluid on day 3 was also higher in nonsurvivors than in survivors (472 mg/dL compared with 180 mg/dL; P < 0.01). These two results suggest that the extent of injury to the endothelial and epithelial barriers of the lung, as reflected by the increased permeability to protein, may be related to the risk for developing fibrosing alveolitis. The higher quantity of protein in the air spaces suggests a parallel to other work. If the endothelial and epithelial barriers are sufficiently injured to preclude effective removal of some of the excess alveolar fluid and protein in the first 12 to 24 hours after the development of the adult respiratory distress syndrome, then the prognosis for survival is poor [16]. The presence of more protein in the distal air spaces, particularly when the protein becomes insoluble and forms hyaline membranes [17], may create a severely altered alveolar environment that leads to an unchecked fibroproliferative response. The precise mechanisms that regulate this transition from an acute to a subacute fibroproliferative lung injury remain largely unknown. However, some interesting experimental work has been done on the mechanisms that regulate repair of the alveolar epithelium [18]; on the potential influence of growth factors and extracellular matrix molecules on the development of pulmonary fibrosis [4, 19]; and on the interaction of cytokines, alveolar epithelial repair, and fibroblast proliferation after acute lung injury [20].

Measurement of a biological marker of collagen synthesis in the lung may be useful for studying the pathogenesis of clinical acute lung injury and for stratifying patients with the adult respiratory distress syndrome for controlled trials of new therapeutic modalities, particularly if measurements of procollagen III in bronchoalveolar lavage fluid are combined with other biochemical and physiologic indices of lung injury. In addition, more basic research is needed to identify the mechanisms that account for the collagen deposition and fibrosing alveolitis that often develop after the accumulation of large quantities of protein-rich edema fluid in the lung after injury to the endothelial and epithelial barriers of the lung.