Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Reduced Surfactant Contributes to Increased Lung Stiffness Induced by Rapid Inspiratory Flow



The mechanism of fast inspiratory flow rate (VI′) induced lung injury is unclear. As fast VI′ increases hysteresis, a measure of surface tension at the air–liquid interface, surfactant release or function may be important. This experimental study examines the contribution of impaired surfactant release or function to dynamic-VILI.


Isolated perfused lungs from male Sprague Dawley rats were randomly allocated to four groups: a long or short inspiratory time (Ti = 0.5 s; slow VI′ or Ti = 0.1 s; fast VI′) at PEEP of 2 or 10 cmH2O. Tidal volume was constant (7 ml/kg), with f = 60 breath/min. Forced impedance mechanics (tissue elastance (Htis), tissue resistance (Gtis) and airway resistance (Raw) were measured at 30, 60 and 90 min following which the lung was lavaged for surfactant phospholipids (PL) and disaturated PL (DSP).


Fast VI′ resulted in a stiffer lung. Concurrently, PL and DSP were decreased in both tubular myelin rich and poor fractions. Phospholipid decreases were similar with PEEP. In a subsequent cohort, laser confocal microscopy-based assessment demonstrated increased cellular injury with increased VI′ at both 30 and 90 min ventilation.


Rapid VI′ may contribute to ventilator induced lung injury (VILI) through reduced surfactant release and/or more rapid reuptake despite unchanged tidal stretch.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5


  1. 1.

    Gattinoni L, Marini JJ, Collino F, Maiolo G, Rapetti F, Tonetti T, Vasques F, Quintel M (2017) The future of mechanical ventilation: lessons from the present and the past. Crit Care 21(1):183. https://doi.org/10.1186/s13054-017-1750-x

  2. 2.

    Gattinoni L, Tonetti T, Cressoni M, Cadringher P, Herrmann P, Moerer O, Protti A, Gotti M, Chiurazzi C, Carlesso E, Chiumello D, Quintel M (2016) Ventilator-related causes of lung injury: the mechanical power. Intensive Care Med 42(10):1567–1575. https://doi.org/10.1007/s00134-016-4505-2

  3. 3.

    Bersten AD, Bryan DL (2005) Ventilator-induced lung injury: do dynamic factors also play a role? Crit Care Med 33(4):907

  4. 4.

    Dreyfuss D, Saumon G (1998) Ventilator-induced lung injury: lessons from experimental studies. Am J Respir Crit Care Med 157(1):294–323. https://doi.org/10.1164/ajrccm.157.1.9604014

  5. 5.

    Protti A, Maraffi T, Milesi M, Votta E, Santini A, Pugni P, Andreis DT, Nicosia F, Zannin E, Gatti S, Vaira V, Ferrero S, Gattinoni L (2016) Role of strain rate in the pathogenesis of ventilator-induced lung edema. Crit Care Med 44(9):e838–e845. https://doi.org/10.1097/ccm.0000000000001718

  6. 6.

    Eissa NT, Ranieri VM, Corbeil C, Chasse M, Robatto FM, Braidy J, Milic-Emili J (1991) Analysis of behavior of the respiratory system in ARDS patients: effects of flow, volume, and time. J Appl Physiol (Bethesda, Md: 1985) 70(6):2719–2729

  7. 7.

    Tschumperlin DJ, Oswari J, Margulies AS (2000) Deformation-induced injury of alveolar epithelial cells. Effect of frequency, duration, and amplitude. Am J Respir Crit Care Med 162 (2 Pt 1):357–362. https://doi.org/10.1164/ajrccm.162.2.9807003

  8. 8.

    Vlahakis NE, Schroeder MA, Pagano RE, Hubmayr RD (2001) Deformation-induced lipid trafficking in alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 280(5):L938–L946

  9. 9.

    Vlahakis NE, Schroeder MA, Pagano RE, Hubmayr RD (2002) Role of deformation-induced lipid trafficking in the prevention of plasma membrane stress failure. Am J Respir Crit Care Med 166(9):1282–1289. https://doi.org/10.1164/rccm.200203-207OC

  10. 10.

    Gajic O, Lee J, Doerr CH, Berrios JC, Myers JL, Hubmayr RD (2003) Ventilator-induced cell wounding and repair in the intact lung. Am J Respir Crit Care Med 167(8):1057–1063. https://doi.org/10.1164/rccm.200208-889OC

  11. 11.

    Davidson KG, Bersten AD, Barr HA, Dowling KD, Nicholas TE, Doyle IR (2000) Lung function, permeability, and surfactant composition in oleic acid-induced acute lung injury in rats. Am J Physiol Lung Cell Mol Physiol 279(6):L1091–L1102

  12. 12.

    Davidson KG, Bersten AD, Barr HA, Dowling KD, Nicholas TE, Doyle IR (2002) Endotoxin induces respiratory failure and increases surfactant turnover and respiration independent of alveolocapillary injury in rats. Am J Respir Crit Care Med 165(11):1516–1525

  13. 13.

    Hantos Z, Daroczy B, Suki B, Nagy S, Fredberg JJ (1992) Input impedance and peripheral inhomogeneity of dog lungs. J Appl Physiol 72(1):168–178

  14. 14.

    Nicholas TE, Power JH, Barr HA (1990) Effect of pattern of breathing on subfractions of surfactant in tissue and alveolar compartments of the adult rat lung. Am J Respir Cell Mol Biol 3(3):251–258

  15. 15.

    Bligh EG, Dyer WJ (1959) A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37(8):911–917

  16. 16.

    Bartlett GR (1959) Phosphorus assay in column chromatography. J Biol Chem 234(3):466–468

  17. 17.

    Mason RJ, Nellenbogen J, Clements JA (1976) Isolation of disaturated phosphatidylcholine with osmium tetroxide. J Lipid Res 17(3):281–284

  18. 18.

    Power JH, Jones ME, Barr HA, Nicholas TE (1986) Analysis of pulmonary phospholipid compartments in the unanesthetized rat during prolonged periods of hyperpnea. Exp Lung Res 11(2):105–128

  19. 19.

    Dixon DL, Barr HA, Bersten AD, Doyle IR (2008) Intracellular storage of surfactant and proinflammatory cytokines in co-cultured alveolar epithelium and macrophages in response to increasing CO2 and cyclic cell stretch. Exp Lung Res 34(1):37–47

  20. 20.

    Samary CS, Silva PL, Gama de Abreu M, Pelosi P, Rocco PR (2016) Ventilator-induced lung injury: power to the mechanical power. Anesthesiology 125(5):1070–1071. https://doi.org/10.1097/aln.0000000000001297

  21. 21.

    Vaporidi K, Voloudakis G, Priniannakis G, Kondili E, Koutsopoulos A, Tsatsanis C, Georgopoulos D (2008) Effects of respiratory rate on ventilator-induced lung injury at a constant PaCO2 in a mouse model of normal lung. Crit Care Med 36(4):1277–1283. https://doi.org/10.1097/CCM.0b013e318169f30e

  22. 22.

    Bach KP, Kuschel CA, Hooper SB, Bertram J, McKnight S, Peachey SE, Zahra VA, Flecknoe SJ, Oliver MH, Wallace MJ, Bloomfield FH (2012) High bias gas flows increase lung injury in the ventilated preterm lamb. PLoS ONE 7(10):e47044. https://doi.org/10.1371/journal.pone.0047044

  23. 23.

    Matute-Bello G, Frevert CW, Martin TR (2008) Animal models of acute lung injury. Am J Physiol Lung Cell Mol Physiol 295(3):L379–L399. https://doi.org/10.1152/ajplung.00010.2008

  24. 24.

    Kawano T, Mori S, Cybulsky M, Burger R, Ballin A, Cutz E, Bryan AC (1987) Effect of granulocyte depletion in a ventilated surfactant-depleted lung. J Appl Physiol (Bethesda, Md: 1985) 62(1):27–33

  25. 25.

    Nicholas TE, Power JH, Barr HA (1982) Surfactant homeostasis in the rat lung during swimming exercise. J Appl Physiol 53(6):1521–1528. https://doi.org/10.1152/jappl.1982.53.6.1521

  26. 26.

    McClenahan JB, Urtnowski A (1967) Effect of ventilation on surfactant, and its turnover rate. J Appl Physiol 23(2):215–220. https://doi.org/10.1152/jappl.1967.23.2.215

  27. 27.

    Faridy EE, Permutt S, Riley RL (1966) Effect of ventilation on surface forces in excised dogs' lungs. J Appl Physiol 21(5):1453–1462. https://doi.org/10.1152/jappl.1966.21.5.1453

  28. 28.

    Nakano H, Magalang UJ, Lee SD, Krasney JA, Farkas GA (2001) Serotonergic modulation of ventilation and upper airway stability in obese Zucker rats. Am J Respir Crit Care Med 163(5):1191–1197. https://doi.org/10.1164/ajrccm.163.5.2004230

  29. 29.

    Dolinay T, Himes BE, Shumyatcher M, Lawrence GG, Margulies SS (2017) Integrated stress response mediates epithelial injury in mechanical ventilation. Am J Respir Cell Mol Biol 57(2):193–203. https://doi.org/10.1165/rcmb.2016-0404OC

Download references


The authors gratefully acknowledge Heather Barr, MSc, and Darren Kennedy, BSc for technical assistance, and Dr Jennifer Clarke for assistance with confocal imaging. This project was supported by the National Health and Medical Research Council (Grant #275565), the Australian and New Zealand College of Anaesthetists (Grant # 06/018) and the Flinders Medical Centre Foundation.


This project was supported by the National Health and Medical Research Council (Grant #275565), the Australian and New Zealand College of Anaesthetists (Grant # 06/018) and the Flinders Medical Centre Foundation.

Author information

ADB, DLD conceived and designed the analysis. MK, KG collected the data. DLD performed the analysis. AB, DLD wrote the paper. AB, MK, KG, DLD revised and approved the final manuscript.

Correspondence to Dani-Louise Dixon.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

All experiments were approved by the Flinders University Animal Welfare Committee and performed according to the National Health and Medical Research Council of Australia Guidelines on Animal Experimentation.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bersten, A.D., Krupa, M., Griggs, K. et al. Reduced Surfactant Contributes to Increased Lung Stiffness Induced by Rapid Inspiratory Flow. Lung 198, 43–52 (2020). https://doi.org/10.1007/s00408-019-00317-1

Download citation


  • Lung mechanics
  • Ventilator induced lung injury
  • Cytokines
  • Inspiratory flow rate
  • Surfactant
  • Confocal microscopy