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Fluid-induced lung injury—role of TRPV4 channels

  • Molecular and Cellular Mechanisms of Disease
  • Published:
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Abstract

Administration of bolus intravenous fluid is associated with respiratory dysfunction and increased mortality, findings with no clear mechanistic explanation. The objective of this study was to examine whether bolus intravenous (i.v.) fluid administration results in acute lung injury in a rat model and further, to examine whether this injury is associated with transient receptor potential vallinoid (TRPV)4 channel function and endothelial inflammatory response. Healthy male Sprague-Dawley rats were administered 60 ml/kg 0.9% saline i.v. over 30 min. Manifestation of acute lung injury was assessed by lung physiology, morphology, and markers of inflammation. The role of TRPV4 channels in fluid-induced lung injury was subsequently examined by the administration of ruthenium red (RR) in this established rat model and again in TRPV4 KO mice. In endothelial cell culture, permeability and P-selectin expression were measured following TRPV4 agonist with and without antagonist; 0.9% saline resulted in an increase in lung water, lavage protein and phospholipase A2, and plasma angiopoietin-2, with worsening in arterial blood oxygen (PaO2), lung elastance, surfactant activity, and lung histological injury score. These effects were ameliorated following i.v. fluid in rats receiving RR. TRPV4 KO mice did not develop lung edema. Expression of P-selectin increased in endothelial cells following administration of a TRPV4 agonist, which was ameliorated by simultaneous addition of RR. Bolus i.v. 0.9% saline resulted in permeability pulmonary edema. Data from ruthenium red, TRPV4 KO mice, and endothelial cell culture suggest activation of TRPV4 and release of angiopoietin 2 and P-selectin as the central mechanism.

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References

  1. Balakrishna S, Song W, Achanta S, Doran SF, Liu B, Kaelberer MM, Yu Z, Sui A, Cheung M, Leishman E, Eidam HS, Ye G, Willette RN, Thorneloe KS, Bradshaw HB, Matalon S, Jordt SE (2014) TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury. Am J Physiol Lung Cell Mol Physiol 307:L158–L172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Barth K, Reh J, Sturrock A, Kasper M (2005) Epithelial vs myofibroblast differentiation in immortal rat lung cell lines—modulating effects of bleomycin. Histochem Cell Biol 124:453–464

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  4. Bihari S, Prakash S, Bersten AD (2013) Post resusicitation fluid boluses in severe sepsis or septic shock: prevalence and efficacy (price study). Shock 40:28–34

    Article  PubMed  Google Scholar 

  5. Bihari S, Prakash S, Bersten AD (2014) Early changes in serum electrolytes and acid-base status with administration of 4% albumin. Intensive Care Med 40:1392–1393

    Article  PubMed  Google Scholar 

  6. Bihari S, Wiersema UF, Schembri D, De Pasquale CG, Dixon DL, Prakash S, Lawrence MD, Bowden JJ, Bersten AD (2015) Bolus intravenous 0.9% saline, but not 4% albumin or 5% glucose, causes interstitial pulmonary edema in healthy subjects. J Appl Physiol (1985) 119:783–792

    Article  CAS  Google Scholar 

  7. Bihari S, Dixon DL, Lawrence MD, Bersten AD (2016) Induced hypernatraemia is protective in acute lung injury. Respir Physiol Neurobiol 227:56–67

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. Calfee CS, Gallagher D, Abbott J, Thompson BT, Matthay MA (2012) Plasma angiopoietin-2 in clinical acute lung injury: prognostic and pathogenetic significance. Crit Care Med 40:1731–1737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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:L1091–L1102

    CAS  PubMed  Google Scholar 

  11. Dixon DL, De Pasquale CG, De Smet HR, Klebe S, Orgeig S, Bersten AD (2009) Reduced surface tension normalizes static lung mechanics in a rodent chronic heart failure model. Am J Respir Crit Care Med 180:181–187

    Article  PubMed  Google Scholar 

  12. Elder AS, Bersten AD, Saccone GT, Dixon DL (2013) Tripeptide feG prevents and ameliorates acute pancreatitis-associated acute lung injury in a rodent model. Chest 143:371–378

    Article  CAS  PubMed  Google Scholar 

  13. Farney RJ, Morris AH, Gardner RM, Armstrong JD Jr (1977) Rebreathing pulmonary capillary and tissue volume in normals after saline infusion. J Appl Physiol Respir Environ Exerc Physiol 43:246–253

    CAS  PubMed  Google Scholar 

  14. Fernandez-Fernandez JM, Andrade YN, Arniges M, Fernandes J, Plata C, Rubio-Moscardo F, Vazquez E, Valverde MA (2008) Functional coupling of TRPV4 cationic channel and large conductance, calcium-dependent potassium channel in human bronchial epithelial cell lines. Pflugers Arch 457:149–159

    Article  CAS  PubMed  Google Scholar 

  15. Fiedler U, Reiss Y, Scharpfenecker M, Grunow V, Koidl S, Thurston G, Gale NW, Witzenrath M, Rosseau S, Suttorp N, Sobke A, Herrmann M, Preissner KT, Vajkoczy P, Augustin HG (2006) Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med 12:235–239

    Article  CAS  PubMed  Google Scholar 

  16. Fishman AP (1973) Shock lung: a distinctive nonentity. Circulation 47:921–923

    Article  CAS  PubMed  Google Scholar 

  17. Forrester JS, Diamond G, Chatterjee K, Swan HJ (1976) Medical therapy of acute myocardial infarction by application of hemodynamic subsets (first of two parts). N Engl J Med 295:1356–1362

    Article  CAS  PubMed  Google Scholar 

  18. Hamanaka K, Jian MY, Weber DS, Alvarez DF, Townsley MI, Al-Mehdi AB, King JA, Liedtke W, Parker JC (2007) TRPV4 initiates the acute calcium-dependent permeability increase during ventilator-induced lung injury in isolated mouse lungs. Am J Physiol Lung Cell Mol Physiol 293:L923–L932

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  20. Hartmannsgruber V, Heyken WT, Kacik M, Kaistha A, Grgic I, Harteneck C, Liedtke W, Hoyer J, Kohler R (2007) Arterial response to shear stress critically depends on endothelial TRPV4 expression. PLoS One 2:e827

    Article  PubMed  PubMed Central  Google Scholar 

  21. Hogg JC, Agarawal JB, Gardiner AJ, Palmer WH, Macklem PT (1972) Distribution of airway resistance with developing pulmonary edema in dogs. J Appl Physiol 32:20–24

    CAS  PubMed  Google Scholar 

  22. Imhof BA, Aurrand-Lions M (2006) Angiogenesis and inflammation face off. Nat Med 12:171–172

    Article  CAS  PubMed  Google Scholar 

  23. Inoue R, Jensen LJ, Shi J, Morita H, Nishida M, Honda A, Ito Y (2006) Transient receptor potential channels in cardiovascular function and disease. Circ Res 99:119–131

    Article  CAS  PubMed  Google Scholar 

  24. Jian MY, King JA, Al-Mehdi AB, Liedtke W, Townsley MI (2008) High vascular pressure-induced lung injury requires P450 epoxygenase-dependent activation of TRPV4. Am J Respir Cell Mol Biol 38:386–392

    Article  CAS  PubMed  Google Scholar 

  25. Jurek SC, Hirano-Kobayashi M, Chiang H, Kohane DS, Matthews BD (2014) Prevention of ventilator-induced lung edema by inhalation of nanoparticles releasing ruthenium red. Am J Respir Cell Mol Biol 50:1107–1117

    Article  PubMed  PubMed Central  Google Scholar 

  26. King LS, Nielsen S, Agre P, Brown RH (2002) Decreased pulmonary vascular permeability in aquaporin-1-null humans. Proc Natl Acad Sci U S A 99:1059–1063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kohler R, Heyken WT, Heinau P, Schubert R, Si H, Kacik M, Busch C, Grgic I, Maier T, Hoyer J (2006) Evidence for a functional role of endothelial transient receptor potential V4 in shear stress-induced vasodilatation. Arterioscler Thromb Vasc Biol 26:1495–1502

    Article  PubMed  Google Scholar 

  28. Kuebler WM, Ying X, Singh B, Issekutz AC, Bhattacharya J (1999) Pressure is proinflammatory in lung venular capillaries. J Clin Invest 104:495–502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Liedtke W, Friedman JM (2003) Abnormal osmotic regulation in trpv4−/− mice. Proc Natl Acad Sci U S A 100:13698–13703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Litwin M, Clark K, Noack L, Furze J, Berndt M, Albelda S, Vadas M, Gamble J (1997) Novel cytokine-independent induction of endothelial adhesion molecules regulated by platelet/endothelial cell adhesion molecule (CD31). J Cell Biol 139:219–228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lorenzo IM, Liedtke W, Sanderson MJ, Valverde MA (2008) TRPV4 channel participates in receptor-operated calcium entry and ciliary beat frequency regulation in mouse airway epithelial cells. Proc Natl Acad Sci U S A 105:12611–12616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lowenstein CJ, Morrell CN, Yamakuchi M (2005) Regulation of Weibel-Palade body exocytosis. Trends Cardiovasc Med 15:302–308

    Article  CAS  PubMed  Google Scholar 

  33. Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P, Akech SO, Nyeko R, Mtove G, Reyburn H, Lang T, Brent B, Evans JA, Tibenderana JK, Crawley J, Russell EC, Levin M, Babiker AG, Gibb DM (2011) Mortality after fluid bolus in African children with severe infection. N Engl J Med 364:2483–2495

    Article  CAS  PubMed  Google Scholar 

  34. Maron MB (1989) Effect of elevated vascular pressure transients on protein permeability in the lung. J Appl Physiol (1985) 67:305–310

    CAS  Google Scholar 

  35. Matthews BD, Thodeti CK, Tytell JD, Mammoto A, Overby DR, Ingber DE (2010) Ultra-rapid activation of TRPV4 ion channels by mechanical forces applied to cell surface beta1 integrins. Integr Biol (Camb) 2:435–442

    Article  CAS  Google Scholar 

  36. Milic-Emili J, Ruff F (1971) Effects of pulmonary congestion and edema on the small airways. Bull Physiopathol Respir (Nancy) 7:1181–1196

    CAS  Google Scholar 

  37. Minnear FL, Barie PS, Malik AB (1983) Effects of transient pulmonary hypertension on pulmonary vascular permeability. J Appl Physiol Respir Environ Exerc Physiol 55:983–989

    CAS  PubMed  Google Scholar 

  38. Mochizuki T, Sokabe T, Araki I, Fujishita K, Shibasaki K, Uchida K, Naruse K, Koizumi S, Takeda M, Tominaga M (2009) The TRPV4 cation channel mediates stretch-evoked Ca2+ influx and ATP release in primary urothelial cell cultures. J Biol Chem 284:21257–21264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Morty RE, Kuebler WM (2014) TRPV4: an exciting new target to promote alveolocapillary barrier function. Am J Physiol Lung Cell Mol Physiol 307:L817–L821

    Article  CAS  PubMed  Google Scholar 

  40. Muir AL, Flenley DC, Kirby BJ, Sudlow MF, Guyatt AR, Brash HM (1975) Cardiorespiratory effects of rapid saline infusion in normal man. J Appl Physiol 38:786–775

    CAS  PubMed  Google Scholar 

  41. Myburgh J, Finfer S, Bellomo R, Billot L, Cass A, Gattas D, Glass P, Lipman J, Liu B, McArthur C (2012) CHEST investigators; Australian and New Zealand intensive care society clinical trials group: hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 367:1901–1911

    Article  CAS  PubMed  Google Scholar 

  42. Nakos G, Kitsiouli E, Hatzidaki E, Koulouras V, Touqui L, Lekka ME (2005) Phospholipases A2 and platelet-activating-factor acetylhydrolase in patients with acute respiratory distress syndrome. Crit Care Med 33:772–779

    Article  CAS  PubMed  Google Scholar 

  43. 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 3:251–258

    Article  CAS  PubMed  Google Scholar 

  44. Pankey EA, Zsombok A, Lasker GF, Kadowitz PJ (2014) Analysis of responses to the TRPV4 agonist GSK1016790A in the pulmonary vascular bed of the intact-chest rat. Am J Physiol Heart Circ Physiol 306:H33–H40

    Article  CAS  PubMed  Google Scholar 

  45. Parker JC, Ivey CL, Tucker JA (1998) Gadolinium prevents high airway pressure-induced permeability increases in isolated rat lungs. J Appl Physiol (1985) 84:1113–1118

    CAS  Google Scholar 

  46. Pellegrino R, Dellaca R, Macklem PT, Aliverti A, Bertini S, Lotti P, Agostoni P, Locatelli A, Brusasco V (2003) Effects of rapid saline infusion on lung mechanics and airway responsiveness in humans. J Appl Physiol (1985) 95:728–734

    Article  Google Scholar 

  47. Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:e45–e45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Rippe B, Townsley M, Thigpen J, Parker JC, Korthuis RJ, Taylor AE (1984) Effects of vascular pressure on the pulmonary microvasculature in isolated dog lungs. J Appl Physiol Respir Environ Exerc Physiol 57:233–239

    CAS  PubMed  Google Scholar 

  49. Romani de Wit T, Rondaij MG, Hordijk PL, Voorberg J, van Mourik JA (2003) Real-time imaging of the dynamics and secretory behavior of Weibel-Palade bodies. Arterioscler Thromb Vasc Biol 23:755–761

    Article  CAS  PubMed  Google Scholar 

  50. Santos CC, Shan Y, Akram A, Slutsky AS, Haitsma JJ (2011) Neuroimmune regulation of ventilator-induced lung injury. Am J Respir Crit Care Med 183:471–482

    Article  PubMed  Google Scholar 

  51. Sidhaye VK, Schweitzer KS, Caterina MJ, Shimoda L, King LS (2008) Shear stress regulates aquaporin-5 and airway epithelial barrier function. Proc Natl Acad Sci 105:3345–3350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Simonsen U, Wandall-Frostholm C, Olivan-Viguera A, Kohler R (2016) Emerging roles of calcium-activated K channels and TRPV4 channels in lung oedema and pulmonary circulatory collapse. Acta Physiol (Oxf)

  53. Solymosi EA, Kaestle-Gembardt SM, Vadasz I, Wang L, Neye N, Chupin CJ, Rozowsky S, Ruehl R, Tabuchi A, Schulz H, Kapus A, Morty RE, Kuebler WM (2013) Chloride transport-driven alveolar fluid secretion is a major contributor to cardiogenic lung edema. Proc Natl Acad Sci U S A 110:E2308–E2316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Staub NC, Nagano H, Pearce ML (1967) Pulmonary edema in dogs, especially the sequence of fluid accumulation in lungs. J Appl Physiol 22:227–240

    CAS  PubMed  Google Scholar 

  55. Sukumaran SV, Singh TU, Parida S, Narasimha Reddy Ch E, Thangamalai R, Kandasamy K, Singh V, Mishra SK (2013) TRPV4 channel activation leads to endothelium-dependent relaxation mediated by nitric oxide and endothelium-derived hyperpolarizing factor in rat pulmonary artery. Pharmacol Res 78:18–27

    Article  CAS  PubMed  Google Scholar 

  56. Sun M, Fu H, Cheng H, Cao Q, Zhao Y, Mou X, Zhang X, Liu X, Ke Y (2012) A dynamic real-time method for monitoring epithelial barrier function in vitro. Anal Biochem 425:96–103

    Article  CAS  PubMed  Google Scholar 

  57. Sun WY, Abeynaike LD, Escarbe S, Smith CD, Pitson SM, Hickey MJ, Bonder CS (2012) Rapid histamine-induced neutrophil recruitment is sphingosine kinase-1 dependent. Am J Pathol 180:1740–1750

    Article  CAS  PubMed  Google Scholar 

  58. Thorneloe KS, Cheung M, Bao W, Alsaid H, Lenhard S, Jian MY, Costell M, Maniscalco-Hauk K, Krawiec JA, Olzinski A, Gordon E, Lozinskaya I, Elefante L, Qin P, Matasic DS, James C, Tunstead J, Donovan B, Kallal L, Waszkiewicz A, Vaidya K, Davenport EA, Larkin J, Burgert M, Casillas LN, Marquis RW, Ye G, Eidam HS, Goodman KB, Toomey JR, Roethke TJ, Jucker BM, Schnackenberg CG, Townsley MI, Lepore JJ, Willette RN (2012) An orally active TRPV4 channel blocker prevents and resolves pulmonary edema induced by heart failure. Sci Transl Med 4:159ra148

    Article  PubMed  Google Scholar 

  59. Villalta PC, Townsley MI (2013) Transient receptor potential channels and regulation of lung endothelial permeability. Pulm Circ 3:802–815

    Article  PubMed  PubMed Central  Google Scholar 

  60. Vriens J, Owsianik G, Fisslthaler B, Suzuki M, Janssens A, Voets T, Morisseau C, Hammock BD, Fleming I, Busse R, Nilius B (2005) Modulation of the Ca2 permeable cation channel TRPV4 by cytochrome P450 epoxygenases in vascular endothelium. Circ Res 97:908–915

    Article  CAS  PubMed  Google Scholar 

  61. Willette RN, Bao W, Nerurkar S, Yue TL, Doe CP, Stankus G, Turner GH, Ju H, Thomas H, Fishman CE, Sulpizio A, Behm DJ, Hoffman S, Lin Z, Lozinskaya I, Casillas LN, Lin M, Trout RE, Votta BJ, Thorneloe K, Lashinger ES, Figueroa DJ, Marquis R, Xu X (2008) Systemic activation of the transient receptor potential vanilloid subtype 4 channel causes endothelial failure and circulatory collapse: part 2. J Pharmacol Exp Ther 326:443–452

    Article  CAS  PubMed  Google Scholar 

  62. Yang X-R, Lin M-J, McIntosh LS, Sham JS (2006) Functional expression of transient receptor potential melastatin-and vanilloid-related channels in pulmonary arterial and aortic smooth muscle. Am J Phys Lung Cell Mol Phys 290:L1267–L1276

    CAS  Google Scholar 

  63. Yang XC, Sachs F (1989) Block of stretch-activated ion channels in Xenopus oocytes by gadolinium and calcium ions. Science 243:1068–1071

    Article  CAS  PubMed  Google Scholar 

  64. Yin J, Hoffmann J, Kaestle SM, Neye N, Wang L, Baeurle J, Liedtke W, Wu S, Kuppe H, Pries AR, Kuebler WM (2008) Negative-feedback loop attenuates hydrostatic lung edema via a cGMP-dependent regulation of transient receptor potential vanilloid 4. Circ Res 102:966–974

    Article  CAS  PubMed  Google Scholar 

  65. Yin J, Kuebler WM (2010) Mechanotransduction by TRP channels: general concepts and specific role in the vasculature. Cell Biochem Biophys 56:1–18

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Critical Care Medicine, Flinders University, Adelaide, 5001, Australia

    Shailesh Bihari, Dani-Louise Dixon, Mark D. Lawrence, Dylan De Bellis & Andrew D Bersten

  2. Intensive and Critical Care Unit, Flinders Medical Centre, Bedford Park, Adelaide, South Australia, 5042, Australia

    Shailesh Bihari, Dani-Louise Dixon & Andrew D Bersten

  3. Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, 5000, Australia

    Claudine S. Bonder & David P. Dimasi

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  1. Shailesh Bihari
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  2. Dani-Louise Dixon
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Contributions

Original idea was done by SB, DLD, ADB. Conduction of experiments was performed by SB, DLD, MDL, DDB, CB, and DPD. Data analysis and interpretation were completed by SB, DLD, MDL, and DDB. Manuscript preparation was done by SB and DLD. Approval of the final version was performed by SB, DLD, MDL, DDB, CB, DPD, and ADB.

Corresponding author

Correspondence to Shailesh Bihari.

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Conflict of interest

The authors declare that they have no conflict of interest.

Sources of support

1. NHMRC - Postgraduate Scholarship (Medical/Dental) APP1038647 to SB.

2. Flinders University - Faculty of Medicine, Nursing and Health Sciences - Small Competitive Research Grants to ADB, DLD, SB.

3. NHMRC GNT1022145 to CSB.

Additional information

Scientific Knowledge on the Subject - Fluid boluses can cause respiratory dysfunction and increased mortality.

What This Study Adds to the Field (Take home message) - Fluid boluses leads to lung injury. This is mediated via activation of TRPV4 channels with an associated increase in systemic angiopoietin 2 levels.

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Bihari, S., Dixon, DL., Lawrence, M.D. et al. Fluid-induced lung injury—role of TRPV4 channels. Pflugers Arch - Eur J Physiol 469, 1121–1134 (2017). https://doi.org/10.1007/s00424-017-1983-1

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  • DOI: https://doi.org/10.1007/s00424-017-1983-1

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