Procollagen Types I and III Aminoterminal Propeptide Levels during Acute Respiratory Distress Syndrome and in Response to Methylprednisolone Treatment

Abstract

Ineffective lung repair in patients with unresolving acute respiratory distress syndrome (ARDS) is accompanied by progressive fibroproliferation, inability to improve lung injury score (LIS), progressive multiple organ dysfunction syndrome (MODS), and an unfavorable outcome. Our aim was to investigate the relationship between fibrogenesis, pulmonary and extrapulmonary organ dysfunction, and outcome during the natural course of ARDS and in response to prolonged methylprednisolone treatment. We investigated 29 patients with ARDS. We obtained serial measurements of plasma and BAL procollagen aminoterminal propeptide type I (PINP) and type III (PIIINP) levels and components of the lung injury score (LIS) and MODS score. A reduction in LIS greater than one point from day 1 to day 7 of ARDS divided patients in improvers (group 1, n = 7) and nonimprovers (n = 22). Nonimprovers included those who were recruited (day 9 +/- 3 of ARDS) into a prospective, randomized, double-blind, placebo-controlled trial investigating prolonged methylprednisolone therapy in unresolving ARDS (group 2, n = 17), and those who died (all by day 10 of ARDS) prior to meeting eligibility criteria for the randomized trial (group 3, n = 5). On day 1 of ARDS, plasma PINP or PIIINP levels were elevated in all patients. By day 7 of ARDS, mean plasma PINP or PIIINP levels were unchanged in group 1 but increased significantly in group 2 (p = 0. 0002) and group 3 (p = 0.03). On day 7, patients with plasma PINP levels less than 100 ng/ml were 2.5 times more likely to survive (95% CI: 0.855-7.314), and patients with plasma PIIINP levels greater than 25 ng/ml were nine times more likely to die (95% CI: 1. 418-55.556). In group 2, patients taking placebo (n = 6) had no change in plasma PINP or PIIINP levels over time, while patients treated with methylprednisolone (n = 11) had a rapid and sustained reduction in mean plasma and bronchoalveolar lavage (BAL) PINP and PIIINP levels. By day 3 of treatment, mean plasma PINP and PIIINP levels (ng/ml) decreased from 100 +/- 9 to 45 +/- 8 (p = 0.0001) and 31 +/- 3 to 12 +/- 3 (p = 0.0008), respectively. After 8 to 15 d of methylprednisolone, mean BAL PINP and PIIINP levels (ng/ml) decreased from 63 +/- 25 to 6 +/- 23 (p = 0.002) and 42 +/- 5 to 10 +/- 3 (p = 0.003), respectively. Estimated partial correlation coefficients indicated that as plasma PINP and PIIINP levels decreased over the first 7 d of methylprednisolone treatment, positive end-expiratory pressure, creatinine, bilirubin, and temperature also decreased, while PaO2:FIO2 increased. In early ARDS, plasma PINP and PIIINP levels are elevated and continue to increase over time in those not improving. Among nonimprovers, those randomized to prolonged methylprednisolone treatment had a rapid and significant reduction in plasma and BAL aminoterminal propeptide levels and similar changes in lung injury and MODS scores. These findings provide additional evidence of an association between biological efficacy and physiologic response during prolonged methylprednisolo...

Circulating Collagen Biomarkers as Indicators of Disease Severity in Pulmonary Arterial Hypertension

“…Studies show that the transpulmonary gradient of procollagen III occur in normal subjects undergoing cardiac catheterization suggesting that normal human lungs can actively synthesize collagen (9). It has been established that elevated procollagen III levels in the serum mirror changes in bronchoalveolar lavage of patients with sarcoidosis (10), interstitial pulmonary fibrosis (11), pneumocystis carinii pneumonia (12), acute lung injury (13), and acute respiratory distress syndrome (14,15) indicating that such parenchymal changes are reflected in peripheral blood samples. These studies suggest that ongoing collagen metabolism in the pulmonary vascular can be assessed by measuring circulating levels of collagen metabolites.…”

The fibroproliferative response in acute respiratory distress syndrome: mechanisms and clinical significance

“…Since lung biopsies are not performed in the majority of patients, investigations utilising bronchoalveolar lavage have provided most of the available information. Pioneering work by several groups in the 1990s demonstrated evidence of robust collagen synthesis (reflected by high levels of N-terminal peptide of type III procollagen) in the lungs of ARDS patients as early as 72 h after the onset of disease [55–57]. Interestingly, the presence of procollagen peptide III correlated with risk for fatal outcome [55, 57].…”

“…Pioneering work by several groups in the 1990s demonstrated evidence of robust collagen synthesis (reflected by high levels of N-terminal peptide of type III procollagen) in the lungs of ARDS patients as early as 72 h after the onset of disease [55–57]. Interestingly, the presence of procollagen peptide III correlated with risk for fatal outcome [55, 57]. Histological assessment of the lungs of ARDS patients, although limited, clearly demonstrates that fibroproliferation is present early in a substantial proportion of patients.…”

Proteomic study of acute respiratory distress syndrome: current knowledge and implications for drug development

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