Acute Lung Injury in Critically Ill Patients: Actin-Scavenger Gelsolin Signals Prolonged Respiratory Failure

Freja Stæhr Holm, Pradeesh Sivapalan, Niels Seersholm, Theis Skovsgaard Itenov, Per Hjort Christensen, Jens-Ulrik Stæhr Jensen, Freja Stæhr Holm, Pradeesh Sivapalan, Niels Seersholm, Theis Skovsgaard Itenov, Per Hjort Christensen, Jens-Ulrik Stæhr Jensen

Abstract

Background: Gelsolin is an actin-scavenger controlling the tissue damage from actin in the blood. Gelsolin levels in circulation drops when tissue damage and corresponding actin release is pronounced due to catabolic conditions. The purpose of this study was to determine if low plasma gelsolin independently predicts a reduced chance of weaning from ventilator-demanding respiratory failure in critically ill patients within 28 days from admission.

Results: This cohort study included 746 critically ill patients with ventilator-demanding respiratory failure from the randomized clinical trial, "Procalcitonin And Survival Study (PASS)." Primary end point was successful weaning from mechanical ventilation within 28 days. We used multivariable Cox regression adjusted for age, sepsis, PaO2/FiO2 ratio and other known and suspected predictors of persistent respiratory failure. Follow-up was complete.For medical patients, baseline-gelsolin below the 25th percentile independently predicted a 40% lower chance of successful weaning within 28 days (HR 0.60, 95% CI 0.46-0.79, P = 0.0002); among surgical patients this end point was not predicted. Low gelsolin levels predicted chance of being "alive and out of intensive care at day 14" for both medical and surgical patients (HR 0.69, 95% CI 0.54-0.89, P = 0.004). Gelsolin levels did not predict 28 day mortality for surgical or medical patients.

Conclusions: Low levels of serum gelsolin independently predict a decreased chance of successful weaning from ventilator within 28 days among medical intensive care patients. This finding has implications for identifying patients who need individualized intervention early in intensive care course to prevent unfavorable lung prognosis in acute respiratory failure.

Trial registration: This is a substudy to the PASS, Clinicaltrials.gov ID: NCT00271752, first registered January 1, 2006.

Conflict of interest statement

Conflicts of Interest: The authors report no conflicts of interest.

Figures

Fig. 1
Fig. 1
Flowchart of patients included.
Fig. 2
Fig. 2
Successful weaning for medical and surgical patients.
Fig. 3
Fig. 3
Kaplan–Meier curve showing mortality.

References

    1. Wunsch H, Angus DC, Harrison DA, Collange O, Fowler R, Hoste EA, de Keizer NF, Kersten A, Linde-Zwirble WT, Sandiumenge A, et al. Variation in critical care services across North America and Western Europe. Crit Care Med 36:2787–2793, 2008.
    1. Wunsch H, Wagner J, Herlim M, Chong DH, Kramer AA, Halpern SD. ICU occupancy and mechanical ventilator use in the United States. Crit Care Med 41:2712–2719, 2013.
    1. Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, Gattinoni L, van Haren F, Larsson A, McAuley DF, et al. Investigators and E. T. Group. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA 315:788–800, 2016.
    1. Saguil A, Fargo M. Acute respiratory distress syndrome: diagnosis and management. Am Fam Physician 85:352–358, 2012.
    1. Sudakov NP, Klimenkov IV, Byvaltsev VA, Nikiforov SB, Konstantinov YM. Extracellular actin in health and disease. Biochemistry (Mosc) 82:1–12, 2017.
    1. Suhler E, Lin W, Yin HL, Lee WM. Decreased plasma gelsolin concentrations in acute liver failure, myocardial infarction, septic shock, and myonecrosis. Crit Care Med 25:594–598, 1997.
    1. Lee WM, Galbraith RM. The extracellular actin-scavenger system and actin toxicity. N Engl J Med 326:1335–1341, 1992.
    1. Janmey PA, Lamb JA, Ezzell RM, Hvidt S, Lind SE. Effects of actin filaments on fibrin clot structure and lysis. Blood 80:928–936, 1992.
    1. Haddad JG, Harper KD, Guoth M, Pietra GG, Sanger JW. Angiopathic consequences of saturating the plasma scavenger system for actin. Proc Natl Acad Sci U S A 87:1381–1385, 1990.
    1. Horvath-Szalai Z, Kustan P, Muhl D, Ludany A, Bugyi B, Koszegi T. Antagonistic sepsis markers: serum gelsolin and actin/gelsolin ratio. Clin Biochem 50:127–133, 2017.
    1. Mounzer KC, Moncure M, Smith YR, Dinubile MJ. Relationship of admission plasma gelsolin levels to clinical outcomes in patients after major trauma. Am J Respir Crit Care Med 160:1673–1681, 1999.
    1. Kwiatkowski DJ, Stossel TP, Orkin SH, Mole JE, Colten HR, Yin HL. Plasma and cytoplasmic gelsolins are encoded by a single gene and contain a duplicated actin-binding domain. Nature 323:455–458, 1986.
    1. Kwiatkowski DJ, Mehl R, Izumo S, Nadal-Ginard B, Yin HL. Muscle is the major source of plasma gelsolin. J Biol Chem 263:8239–8243, 1988.
    1. Christofidou-Solomidou M, Scherpereel A, Solomides CC, Muzykantov VR, Machtay M, Albelda SM, DiNubile MJ. Changes in plasma gelsolin concentration during acute oxidant lung injury in mice. Lung 180:91–104, 2002.
    1. Lind SE, Smith DB, Janmey PA, Stossel TP. Depression of gelsolin levels and detection of gelsolin-actin complexes in plasma of patients with acute lung injury. Am Rev Respir Dis 138:429–434, 1988.
    1. Bucki R, Levental I, Kulakowska A, Janmey PA. Plasma gelsolin: function, prognostic value, and potential therapeutic use. Curr Protein Pept Sci 9:541–551, 2008.
    1. Guo XC, Luo BY, Li XF, Yang DG, Zheng XN, Zhang K. Plasma gelsolin levels and 1-year mortality after first-ever ischemic stroke. J Crit Care 26:608–612, 2011.
    1. Xianhui L, Pinglian L, Xiaojuan W, Wei C, Yong Y, Feng R, Peng S, Gang X. The association between plasma gelsolin level and prognosis of burn patients. Burns 40:1552–1555, 2014.
    1. Wang H, Cheng B, Chen Q, Wu S, Lv C, Xie G, Jin Y, Fang X. Time course of plasma gelsolin concentrations during severe sepsis in critically ill surgical patients. Crit Care 12:R106, 2008.
    1. Osborn TM, Verdrengh M, Stossel TP, Tarkowski A, Bokarewa M. Decreased levels of the gelsolin plasma isoform in patients with rheumatoid arthritis. Arthritis Res Ther 10:R117, 2008.
    1. Kulakowska A, Ciccarelli NJ, Wen Q, Mroczko B, Drozdowski W, Szmitkowski M, Janmey PA, Bucki R. Hypogelsolinemia, a disorder of the extracellular actin scavenger system, in patients with multiple sclerosis. BMC Neurol 10:107, 2010.
    1. Lee PS, Drager LR, Stossel TP, Moore FD, Rogers SO. Relationship of plasma gelsolin levels to outcomes in critically ill surgical patients. Ann Surg 243:399–403, 2006.
    1. Smith DB, Janmey PA, Herbert TJ, Lind SE. Quantitative measurement of plasma gelsolin and its incorporation into fibrin clots. J Lab Clin Med 110:189–195, 1987.
    1. Eisner MD, Parsons P, Matthay MA, Ware L, Greene K. Plasma surfactant protein levels and clinical outcomes in patients with acute lung injury. Thorax 58:983–988, 2003.
    1. Hartl D, Griese M. Surfactant protein D in human lung diseases. Eur J Clin Invest 36:423–435, 2006.
    1. Jensen JS, Itenov TS, Thormar KM, Hein L, Mohr TT, Andersen MH, Loken J, Tousi H, Lundgren B, Boesen HC, et al. Prediction of non-recovery from ventilator-demanding acute respiratory failure, ARDS and death using lung damage biomarkers: data from a 1200-patient critical care randomized trial. Ann Intensive Care 6:114, 2016.
    1. Takano S, Kimura S, Ohdama S, Aoki N. Plasma thrombomodulin in health and diseases. Blood 76:2024–2029, 1990.
    1. Jensen JS, Hein L, Lundgren B, Bestle MH, Mohr TT, Andersen MH, Thornberg KJ, Loken J, Steensen M, Fox Z, et al. Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: a randomized trial. Crit Care Med 39:2048–2058, 2011.
    1. European Medicines Agency: Note for Guidance on Good Clinical Practice, EMEA (European Medicines Agency). Accessed January 5, 2014.
    1. Christensen PH, Grønkjær K. Quantitative determination of human serum gelsolin. Development and validation of an automated turbidimetric immunoassay. Clin Chim Acta 355 (Supp l):S1–S483, 2005.
    1. Li B, Zhao X, Li S. Serum procalcitonin level and mortality risk in critically ill patients with ventilator-associated pneumonia. Cell Physiol Biochem 37:1967–1972, 2015.
    1. Kruse JA, Thill-Baharozian MC, Carlson RW. Comparison of clinical assessment with APACHE II for predicting mortality risk in patients admitted to a medical intensive care unit. JAMA 260:1739–1742, 1988.
    1. Yang Z, Chiou TT, Stossel TP, Kobzik L. Plasma gelsolin improves lung host defense against pneumonia by enhancing macrophage NOS3 function. Am J Physiol Lung Cell Mol Physiol 309:L11–L16, 2015.
    1. Rothenbach PA, Dahl B, Schwartz JJ, O’Keefe GE, Yamamoto M, Lee WM, Horton JW, Yin HL, Turnage RH. Recombinant plasma gelsolin infusion attenuates burn-induced pulmonary microvascular dysfunction. J Appl Physiol (1985) 96:25–31, 2004.
    1. Cohen TS, Bucki R, Byfield FJ, Ciccarelli NJ, Rosenberg B, DiNubile MJ, Janmey PA, Margulies SS. Therapeutic potential of plasma gelsolin administration in a rat model of sepsis. Cytokine 54:235–238, 2011.
    1. Bersten AD, Soni N, Oh TE. Oh's intensive care manual. 5th ed.Philadelphia, USA: Butterworth-Heinemann; 2004.

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