Skip to main content
SpringerLink
Log in

Hyaluronic Acid

Perspectives in lung diseases

  • Chapter
  • First Online:
Book cover Heparin - A Century of Progress

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 207))

Abstract

Hyaluronic acid (HA) is a non-sulphated glycosaminoglycan. It is a natural polymer characterised by a coiled linear chain in particularly well-hydrated configuration composed of repeating disaccaride units. In mammals, its molecular weight can be extremely wide, ranging from 20 to 4,000 kDa. High molecular mass forms are provided with anti-inflammatory properties. A unique characteristic of HA is hydration (up to 6,000 molecules water/molecule of HA) with a major role in the regulation of fluid balance in the interstitium, a fundamental activity on the amorphous colloidal matrix gluing connective cell and fibers, and many other biological functions including lubrication, solute transport and microcirculatory exchange. HA has been widely used in the treatment of eye, ear, joint and skin disorders; in the last 15 years HA has been also proposed successfully in the treatment of a number of lung diseases in vitro, experimental animals and humans. In particular, inhaled HA at relatively high molecular weight has been proven to prevent bronchoconstiction induced in asthmatics by direct and indirect challenges such as inhalation of methacholine, inhalation of ultrasonically nebulised distilled water, muscular exercise. More recently, in patrients affected by chronic obstructive pulmonary diseases, we have demonstrated that repeated administrations of inhaled HA (daily, for 8 weaks) induce significant increase in bronchial patency as well as progressive lung deflation with decrease of residual volume. In conclusion there are elements that can let us state that is perhaps time to change the focus to connective tissue and extracellular matrix substances such as HA, in order to prevent and treat chronic lung diseases.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Ahmed T, Abraham WM, D’Brot J (1992) Effects of inhaled heparin on immunologic and non-immunologic bronchoconstriction responses in sheep. Am Rev Respir Dis 145:566–570

    PubMed  CAS  Google Scholar 

  • Ahmed T, Garrigo J, Danta I (1993) Preventing bronchoconsriction in exercise-induced asthma with inhaled heparin. N Engl J Med 329:90–95

    Article  PubMed  CAS  Google Scholar 

  • Ahmed T, Gonzales BJ, Danta I (1999) Prevention of exercise-induced bronchoconstriction by inhaled low molecular weight heparin. Am J Respir Crit Care Med 160:576–581

    PubMed  CAS  Google Scholar 

  • Ahmed T, Hallmon J, Abraham WM (1991) The effect of heparin on immunologically-induced tracheal smooth muscle contraction in allergic sheep. Am Rev Respir Dis 143(Suppl):A360, abstract

    Google Scholar 

  • Ahmed T, Syriste T, Mendelssohn R, Sorace D, Mansour E, Lansing M, Abraham WM, Robinson MJ (1994) Heparin prevents antigen-induced airway hyperresponsiveness: interference with !P3-mediated mast cell degranulation? J Appl Physiol 76:893–901

    Article  PubMed  CAS  Google Scholar 

  • Allegra L, Abraham WM, Fasano V, Petrigni G (2008) Methacholine challenge in asthmatics is protected by aerosolised hyaluronan at high (1,000 kDa) but not low (300 kDa) molecular weight. Ital J Chest Dis 62:297–301

    Google Scholar 

  • Allegra L, Bianco S, Petrigni G, Robuschi M (1974) Lo sforzo muscolare e la nebulizzazione ultrasonica di H2O come test di provocazione aspecifica del broncospasmo. In: Pasargiklian M, Bocca E (eds) Progressi in Medicina Respiratoria. Terme di Sirmione, Sirmione, pp 81–86

    Google Scholar 

  • Allegra L, Bianco S (1980) Non-specific bronchoreactivity obtained with an ultrasonic aerosol of distilled water. Eur J Respir Dis 61(Suppl 106):41–49

    Google Scholar 

  • Allegra L, Dal Negro R (1993) Physical agents in bronchial provocation tests: nebulised hypoosmolar aerosol. In: Allegra L, Braga PC, Dal Negro R (eds) Methods in asthmology. Springer, Berlin, pp 219–225

    Google Scholar 

  • Allegra L, Della Patrona S, Comi A, Fasano V, Longo L, Terzano C, Petrigni G (2006) Aerosols of hyaluronan partially prevent bronchoconstriction induced by ultrasonically nebulised distilled water in asthmatics. Ital J Chest Dis 60:243–248

    Google Scholar 

  • American Thoracic Society (2000) Guidelines for methacholine and exercise challenge testing 1999. Am J Respir Crit Care Med 161:309–329

    Google Scholar 

  • Anderson SD (1985) Bronchial challenge by ultrasonically nebulized aerosols. Clin Rev Allergy 3:427–439

    PubMed  CAS  Google Scholar 

  • Anderson SD, Brannan JD (2004) Methods for “indirect” challenge tests including exercise, eucapnic voluntary hyperpnea, and hypertonic aerosols. Paediatr Drugs 6:161–175

    Article  PubMed  Google Scholar 

  • Anderson SD, Schoeffel RE, Finney M (1983) Evaluation of ultrasonic distilled water for provocation testing in patients with asthma. Thorax 38:284–291

    Article  PubMed  CAS  Google Scholar 

  • Anderson SD, Schoeffel RE, Follet R, Perry CP, Daviskas E, Kendall M (1982) Sensitivity to heat and water loss at rest and during exercise in asthmatic patients. Eur J Respir Dis 63:459–471

    PubMed  CAS  Google Scholar 

  • Baccarani-Contri M, Vincenzi D, Cicchetti F, Mori G, Pasquali-Ronchetti I (1990) Immunocytochemical localization of proteoglycans within normal elastin fibers. Eur J Cell Biol 53:305–312

    PubMed  CAS  Google Scholar 

  • Balasz A, Laurent TC, Jeanlo RW (1986) Nomenclature of hyaluronic acid. Biochem J 235:903, abstract

    Google Scholar 

  • Bert JL, Pierce RH (1984) The interstitium and microvascular exchange. In: Renkin EM (ed) Handbook of physiology. Section 2: the cardiovascular system, Vol. IV, Pt 1: Microcirculation. American Physiological Society, Bethesda, pp 521–547

    Google Scholar 

  • Bhattacharya J, Cruz T, Bhattacharya S, Bray BA (1989) Hyaluronan affects extravascular water in lungs of unanesthetized rabbits. J Appl Physiol 66:2595–2599

    PubMed  CAS  Google Scholar 

  • Blackwood RA, Cantor JO, Moret J, Mandl I, Turino GM (1983) Glycosaminoglycan synthesis in endotoxin-induced lung injury. Proc Soc Exp Biol Med 174:343–349

    PubMed  CAS  Google Scholar 

  • Bothner H, Wyk O (1987) Rheology of hyaluronate. Acta Otorinolaryngol 442(suppl):25–30

    Article  CAS  Google Scholar 

  • Braya PC, Allegra L. (1988) Methods in Bronchial Mucology, Raven Press, New York

    Google Scholar 

  • Brown RA, Allegra L, Matera MG, Page CP, Cazzola M (2006) Additional clinical benefits of enoxaparin in COPD patients receiving salmeterol and fluticasone propionate in combination. Pulm Pharmacol Ther 19:419–424

    Article  PubMed  CAS  Google Scholar 

  • Bush A (2008) How early do airway inflammation and remodelling occur? Allergol Int 57:11–19

    Article  PubMed  Google Scholar 

  • Cade JF, Pain MCF (1972) Lung function in provoked asthma: response to inhaled urea, methacholine and isoprenaline. Clin Sci 43:759–769

    PubMed  CAS  Google Scholar 

  • Cantor JO, Cerreta JM, Keller S, Turino GM (1995) Modulation of airspace enlargement in elastase-induced emphysema by intratracheal instillment of hyaluronidase and hyaluronic acid. Exp Lung Res 21:423–436

    Article  PubMed  CAS  Google Scholar 

  • Cheney FW jr, Butler J (1968) The effect of ultrasonically produced aerosols on airway resistance in man. Anesthesiology 29:1099–1106

    Article  PubMed  Google Scholar 

  • Cheney FW jr, Butler J (1970) The effects of ultrasonica aerosols on the total respiratory resistance in the intubated patient. Anesthesiology 32:456–458

    Article  PubMed  CAS  Google Scholar 

  • Cleland RL, Wang JL (1970) Tonic polysaccharides. III: dilute solution properties of hyaluronic acid fraction. Biopolymers 9:799–810

    Article  PubMed  CAS  Google Scholar 

  • Dahl R (2008) Glycosaminoglycans: therapeutic opportunities for hyaluronan in respiratory diseases. Ital J Chest Dis 62:289–296

    Google Scholar 

  • Daviskas E, Anderson SD (2006) Hyperosmolar agents and clearance of mucus in the diseased airway. J Aerosol Med 19:100–109

    Article  PubMed  CAS  Google Scholar 

  • Dentener MA, Vernooy JH, Hendriks S et al (2005) Enhanced levels of hyaluronan in lungs of patients with COPD: relationship with lung function and local inflammation. Thorax 60:114–119

    Article  PubMed  CAS  Google Scholar 

  • Elwood RK, Hogg JC, Pare PD (1982) Airway response to osmolar challenge in asthma. Am Rev Respir Dis 61(Suppl):125, abstract

    Google Scholar 

  • Eschenbacher WL, Boushey HA, Sheppard D (1984) Alteration in osmolarità of inhaled aerosols cause bronchoconstriction and cough, but of a permanent anion causes cough alone. Am Rev Respir Dis 129:211–215

    PubMed  CAS  Google Scholar 

  • Fraser JR, Laurent TC, Laurent UB (1997) Hyaluronan: its nature, distribution, function and turnover. J Intern Med 242:27–33

    Article  PubMed  CAS  Google Scholar 

  • Fraser JRE, Kimpton WG, Laurent TC, Cahill RN, Vakakis N (1988) Uptake and degradation of hyaluronan in lymphatic tissue. Biochem J 256:153–158

    PubMed  CAS  Google Scholar 

  • Fryer A, Huang YC, Rao G, Jacobi D, Mancilla E, Whorton R et al (1997) Selective O- desulfation produces nonanticoagulant heparin that retains pharmacological activity in the lung. J Pharmacol Exp Ther 282:208–219

    PubMed  CAS  Google Scholar 

  • Garrigo J, Danta I, Ahmed T (1996) Time course of the protective effect of inhaled heparin on exercise-induced asthma. Am J Respir Crit Care Med 153:1702–1707

    PubMed  CAS  Google Scholar 

  • Goh LT (1998) Effect of colture conditions on rates of intrinsic hyaluronic acid production by Streptococcus equi spp Zooepidermicus. Biotechnol Lett 16:507–512

    Google Scholar 

  • Goldberg EP, Burns JW, Jacobi Y (1993) Prevention of postoperative adhesion to precoating tissues with diluted sodium hyaluronate solutions. Prog Clin Biol Res 381:191–204

    PubMed  CAS  Google Scholar 

  • Granger HJ, Laine GA, Barnes JE, Lewis RE (1984) Dynamics and control of transmicrovascular fluid exchange. In: Staub NC et al (eds) Edema. Raven, New York, pp 198–228

    Google Scholar 

  • Granger HJ (1981) Physicochemical properties of the extracellular matrix. In: Hargens AR (ed) Tissues fluid pressure and composition. Williams & Wilkins, Baltimore, pp 43–61

    Google Scholar 

  • Hallgren R, Eklund A, Engstrom-Laurent A et al (1985) Hyaluronate in bronchoalveolar lavage fluid: a new marker in sarcoidosis reflecting pulmonary disease. Br Med J 290:1778–1781

    Article  CAS  Google Scholar 

  • Haynes BF, Hua-Xin L, Patton KL (1991) The transmembrane hyaluronate receptor (CD44): multiple functions, multiple forms. Cancer Cells 3:347–350

    PubMed  CAS  Google Scholar 

  • Hogg JC, Eggleston PA (1984) Is asthma an epithelial disease? Am Rev Respir Dis 129:207–208

    PubMed  CAS  Google Scholar 

  • Itano N, Sawai T, Yoshida M et al (1999) Three isoforms of mammalian hyaluronan synthases have distinct enzymatic properties. J Biol Chem 274:25085–25092

    Article  PubMed  CAS  Google Scholar 

  • Johnson PR, Roth M, Tamm M et al (2001) Airway smooth muscle cell proliferation is increased in asthma. Am J Respir Crit Care Med 164:474–477

    PubMed  CAS  Google Scholar 

  • Keity CM, Whittaker SP, Grant MF, Shuttleworth CA (1992) Type VI collagen microfibrils: evidence for a structural association with hyaluronan. J Cell Biol 118:979–990

    Article  Google Scholar 

  • King SR, Hickerson WL, Proctor KG (1991) Beneficial actions of exogenous hyaluronic acid on wound healing. Surgery 109:76–84

    PubMed  CAS  Google Scholar 

  • Klagas I, Goulet S, Karakiulakis G, Zhong J, Baraket M, Black JL, Papakonstantinou E, Royh M (2009) Decreased hyaluronan in airway smooth muscle cells from patients with asthma and COPD. Eur Respir J 34:616–628

    Article  PubMed  CAS  Google Scholar 

  • Kunz LIZ, van Rengen ELJ, Sterk PJ (2006) Inhaled hyaluronic acid against exercise-induced broncho-constriction in asthma. Pulm Pharmacol Ther 19:286–291

    Google Scholar 

  • Laurent TC (1970) Structure of hyaluronic acid. In: Balasz EA (ed) Chemistry and molecular biology of the intercellular matrix. Academic, London, pp 703–732

    Google Scholar 

  • Laurent UGB, Reed RK (1991) Turnover of hyaluronan in the tissue. Adv Drug Deliv Rev 7:237–256

    Article  CAS  Google Scholar 

  • Lever R, Page C (2001) Glycosaminoglycans, airways inflammation and bronchial inflammation. Pulm Pharmacol Ther 14:249–254

    Article  PubMed  CAS  Google Scholar 

  • Magyar P, Dervaderics M, Tòth A, Lantos A (1983) Inhalation of hypertonic potassium chloride solution: a specific bronchial challenge for asthma. Ital J Chest Dis 37:29–34

    Google Scholar 

  • Marchette LC, Marchette BE, Abraham WM, Wanner A (1985) The effect of systemic hydration on normal and impaired mucociliary function. Pediatr Pulmonol 1:107–111

    Article  PubMed  CAS  Google Scholar 

  • McFadden ER, Lenner KAM, Strohl KP (1986) Postexertional airway rewarming and thermally induced asthma. New insights into pathophysiology and possible pathogenesis. J Clin Invest 78:18–25

    Article  PubMed  Google Scholar 

  • Meyer K, Palmer JW (1934) The polysaccharide in vitreous humour. J Biol Chem 107:629–634

    CAS  Google Scholar 

  • Monzon ME, Casalino-Matsuda SM, Forteza RM (2006) Identification of glycosaminoglycans in human airway secretions. Am J Respir Cell Mol Biol 34:135–141

    Article  PubMed  CAS  Google Scholar 

  • Papakonstantinou E, Karakiulakis G, Eickelberg O et al (1998) A 340 kDa hyaluronic acid secreted by human vascular smooth muscle cells regulates their proliferation and migration. Glycobiology 8:821–830

    Article  PubMed  CAS  Google Scholar 

  • Petrigni G, Allegra L (2006) Aerosolised hyaluronic acid prevents exercise-induced bronchoconstriction, suggesting novel hypotheses on the correction of matrix defects in asthma. Pulm Pharmacol Ther 19:166–171

    Article  PubMed  CAS  Google Scholar 

  • Poole AR, Dieppe P (1994) Biological markers in rheumatoid arthritis. Semin Arthritis Rheum 23:17–31

    Article  PubMed  CAS  Google Scholar 

  • Postma DS, Timens W (2006) Remodelling in asthma and chronic obstructive pulmonary disease. Proc Am Thor Soc 3:434–439

    Article  CAS  Google Scholar 

  • Potter PC, Klein M, Weinberg EG (1991) Hydration in severe acute asthma. Arch Dis Child 66:216–299

    Article  PubMed  CAS  Google Scholar 

  • Reed RK, Bowen BD, Bert JL (1989) Microvascular exchange and interstitial volume regulation in the rat: implication of the model. Am J Physiol 257H:2081–2091

    Google Scholar 

  • Reed RK, Laurent UGB (1992) Turnover of hyaluronan in the microcirculation. Am Rev Respir Dis 146:S37–S39

    PubMed  CAS  Google Scholar 

  • Schmid K, Grundboeck-Jusco J, Kimura A, Tschopp FA, Zollinger R, Binette JP, Lewis W, Hayashi S (1982) The distribution of the glycosaminoglycans in the anatomic components of the lung and the changes in concentration of these macromolecules during development and aging. Biochem Biophys Acta 716:178–187

    Article  PubMed  CAS  Google Scholar 

  • Schoeffel RE, Anderson SD, Altounyan RE (1981) Bronchial hyperreactity in response to inhalation of ultrasonically nebulized solutions of distilled water and saline. Br Med J 283:1285–1287

    Article  CAS  Google Scholar 

  • Scuri M, Abraham WM, Botvinnikova Y, Forteza R (2001) Hyaluronic acid blocks porcine pancreatic elastase (PPE)-induced broncho-constriction in sheep. Am J Crit Care Med 164:1855–1859

    CAS  Google Scholar 

  • Scuri M, Abraham WM (2003) Hyaluronan blocks human neutrophil elastase (HNE)-induced air way responses in sheep. Pulm Pharmacol Ther 16:335–340

    Article  PubMed  CAS  Google Scholar 

  • Scuri M, Sabater J, Abraham WM (2007) Hyaluronan blocks porcine pancreatic elastase-induced mucociliary dysfunction in allergic sheep. J Appl Physiol 102:2324–2331

    Article  PubMed  CAS  Google Scholar 

  • Shaw RJ, Anderson SD, Durham SR, Taylor KM, Schoeffel RE, Green W, Torzillo P, Kay AB (1985) Mediators of hypersensitivity and “fog”-induced asthma. Allergy 40:48–57

    Article  PubMed  CAS  Google Scholar 

  • Sheppard D, Rtzk N, Boushey HA (1983) Mechanism of cough and bronchoconstriction induced by distilled water aerosol. Am Rev Respir Dis 127:691–694

    PubMed  CAS  Google Scholar 

  • Sheppard D, Eschenbacher WL (1984) Respiratory water loss as a stimulus to exercise-induced bronchoconstriction. J Allergy Clin Immunol 73:640–642

    Article  PubMed  CAS  Google Scholar 

  • Singleton R, Moel DI, Cohn RA (1986) Preliminary observation of impaired water excretion in treated status asthmaticus. Am J Dis Child 140:59–61

    PubMed  CAS  Google Scholar 

  • Smedrson B, Perthof H, Gustavson S, Laurent TC (1990) Scavenger function of the liver endothelial cell. Biochem J 266:313–327

    Google Scholar 

  • Toole BP (1990) Hyaluronan and its binding proteins, hyaladerins. Curr Opin Cell Biol 2:839–844

    Article  PubMed  CAS  Google Scholar 

  • Toole BP (1991) Glycosaminoglycans and morphogenesis. In: Hay ED (ed) Cell biology and extracellular M2trix. Plenum, New York, pp 259–294

    Google Scholar 

  • Toole BP (2004) Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer 4:528–539

    Article  PubMed  CAS  Google Scholar 

  • Tranfa CM, Vatrella A, Parrella R, Pelaia G, Bariffi F, Marsico S (2001) Effect of inhaled heparin on water-induced bronchoconstriction in allergic asthmatics. Eur J Clin Pharmacol 57:59

    Article  Google Scholar 

  • Turino GM (1986) The pulmonary parenchyma: a dynamic matrix (J. Burns Amberson lecture). Am Rev Respir Dis 132:1324–1334

    Google Scholar 

  • Turino GM (2003) Hyaluronan in respiratory injury and repair. Am J Respir Crit Care Med 167:1169–1175

    Article  PubMed  Google Scholar 

  • Underhill CB (1992) CD44: the hyaluronan receptor. J Cell Sci 103:193–198

    Google Scholar 

  • Valerio G, Salerno FG, Bracciale P (2007) The i.v. infusion of mannitol decreases air way responsiveness to methacholine in asthma. Respir Physiol Neurobiol 156:374–377

    Article  PubMed  CAS  Google Scholar 

  • Venge P, Pedersen B, Hakansson L, Hallgren R, Lindblad G, Dahl R (1996) Subcutaneous administration of hyaluronan reduces the number of infectious exacerbations in patients with chronic bronchitis. Am J Respir Crit Care Med 153:312–316

    PubMed  CAS  Google Scholar 

  • Vitanzo PC jr, Sennett BJ (2006) Hyaluronans: is clinical effectiveness dependent on molecular weight? Am J Orthop 35:421–428

    PubMed  Google Scholar 

  • Yang B, Zhang L, Turley EA (1993) Identification of two hyaluronan-binding domains in the hyaluronan receptor RHAMM. J Biol Chem 268:8617–8623

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Università degli Studi, IRCCS Fondazione Ca’ Granda, Ospedale Policlinico, Via Francesco Sforza 35, 20122, Milano, Italy

    Luigi Allegra & Giuseppe Petrigni

  2. IRCCS Fondazione S. Maugeri, Istituto Scientifico di Riabilitazione, Via Roncaccio 16, 21049, Tradate, Varese, Italy

    Sabrina Della Patrona

Authors
  1. Luigi Allegra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sabrina Della Patrona
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Giuseppe Petrigni
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Luigi Allegra .

Editor information

Editors and Affiliations

  1. School of Pharmacy, University of London, Brunswick Square 29-39, London, WC1N 1AX, United Kingdom

    Rebecca Lever

  2. Standards and Control, National Institute for Biological, Blanche Lane, Potters Bar, Herts., EN6 3QG, United Kingdom

    Barbara Mulloy

  3. King's College London, Sackler Inst. Pulmonary Pharmacology, Waterloo Campus, London, SE1 9NH, United Kingdom

    Clive P. Page

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Allegra, L., Patrona, S.D., Petrigni, G. (2012). Hyaluronic Acid. In: Lever, R., Mulloy, B., Page, C. (eds) Heparin - A Century of Progress. Handbook of Experimental Pharmacology, vol 207. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-23056-1_17

Download citation

Publish with us

Policies and ethics

Search

Navigation