title: Serum MMP-8 and TIMP-1 in critically ill patients with acute respiratory failure: TIMP-1 is associated with increased 90-day mortality.
abstract: BACKGROUND
  Matrix metalloproteinases (MMPs) likely have an important role in the pathophysiology of acute lung injury. In a recent study, high matrix metalloproteinases (MMP-8) levels in tracheal aspirates of pediatric acute respiratory distress syndrome (ARDS) patients were associated with worse outcome. In patients with sepsis, an imbalance between MMPs and their tissue inhibitors (TIMPs) has been associated with impaired survival. We hypothesized that the elevated systemic MMP-8 and TIMP-1 are associated with worse outcome in acute respiratory failure.
  
  
  METHODS
  This was a substudy of the observational FINNALI study conducted in 25 Finnish intensive care units over an 8-week period. All patients older than 16 years requiring mechanical ventilation for >6 hours were included. MMP-8 and TIMP-1 levels were analyzed from blood samples taken on enrollment in the study and 48 hours later. Laboratory analyses were performed by using immunofluorometric assay for MMP-8 and ELISA for TIMP-1. MMP-8 and TIMP-1 levels were compared between 90-day survivors and nonsurvivors. Survival was compared in quartiles based on TIMP-1 levels, and ROC analysis was performed to calculate areas under the curves. The relationship between MMP-8 and TIMP-1 levels and degree of hypoxemia was examined.
  
  
  RESULTS
  The final analyses included 563 patients. Admission TIMP-1 levels were higher in nonsurvivors, median 367 ng/mL (interquartile range 199-562), than survivors, median 240 ng/mL (interquartile range 142-412), WMWodds 1.68 (95% confidence interval [CI], 1.43-2.08). MMP-8 levels may have differed between survivors and nonsurvivors, WMWodds 1.20 (95% CI, 1.01-1.43), but no difference was found in the MMP-8/TIMP-1 molar ratio, WMWodds 0.83 (95% CI, 0.67-1.04). Difference in survival between quartiles based on TIMP-1 was significant (log-rank, P < 0.001). ROC analysis produced an area under the curve 0.63 (95% CI, 0.58-0.69) for TIMP-1. TIMP-1 was associated with severity of hypoxemia. TIMP-1 levels were higher in an ARDS subgroup than in the whole cohort, WMWodds 1.65 (95% CI, 1.15-2.44).
  
  
  CONCLUSIONS
  MMP-8 levels were possibly higher in 90-day nonsurvivors but performed poorly in predicting outcome. Increased systemic levels of TIMP-1 were associated with more severe hypoxemia and worse outcome in a large cohort of mechanically ventilated critically ill patients and in a subgroup of ARDS patients.
authors.affiliation: From the *Intensive Care Units, Helsinki University Hospital; †Department of Oral and Maxillofacial Diseases, Helsinki University Hospital and Biomedicum Helsinki, Helsinki; ‡Intensive Care Unit, South Carelia Central Hospital, Lappeenranta; and §Department of Anesthesiology and Intensive Care, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Hästbacka
authors.forename: Rita
authors.initials: R
authors.lastname: Linko
authors.forename: Taina
authors.initials: T
authors.lastname: Tervahartiala
authors.forename: Tero
authors.initials: T
authors.lastname: Varpula
authors.forename: Seppo
authors.initials: S
authors.lastname: Hovilehto
authors.forename: Ilkka
authors.initials: I
authors.lastname: Parviainen
authors.forename: Suvi T
authors.initials: ST
authors.lastname: Vaara
authors.forename: Timo
authors.initials: T
authors.lastname: Sorsa
authors.forename: Ville
authors.initials: V
authors.lastname: Pettilä
mesh_terms: D000208:Acute Disease; D000368:Aged; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D016638:Critical Illness / Q000401:mortality*; D003428:Cross Infection / Q000097:blood / Q000401:mortality; D017558:Elective Surgical Procedures; D004632:Emergency Medical Services; D023381:Endpoint Determination; D005260:Female; D017052:Hospital Mortality; D006801:Humans; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000097:blood*; D008875:Middle Aged; D012372:ROC Curve; D012121:Respiration, Artificial; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000401:mortality; D012129:Respiratory Function Tests; D012131:Respiratory Insufficiency / Q000097:blood* / Q000401:mortality; D018805:Sepsis / Q000097:blood / Q000401:mortality; D017741:Survivors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*
chemical_list: D015415:Biomarkers; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; C488762:MMP8 protein, human; D020784:Matrix Metalloproteinase 8