Changes in taste perception in patients with interstitial lung disease: The need for new diets and food products.

Viktor Proesmans
Welke voedingsstoffen hebben een effect op interstitiële longziektes, wat voor dieet kunnen we maken om mensen verder te ondersteunen in hun complex ziekteproces?

Voeding als medicijn tegen longziektes

Voeding als medicijn tegen longziektes.

 

‘Laat uw voeding uw medicijn zijn en uw medicijn uw voeding’. Het is een citaat van Hippocrates dat al meer dan 2000 jaar oud is. Zelfs bij de oude Grieken was de relatie tussen een gezond dieet en een goede gezondheid bekend. Toch is het zo dat vandaag de dag voeding en medicatie in de medische wereld grotendeels gescheiden worden gehouden. Naar een diëtist gaan omdat je lijdt aan een longziekte klinkt dan ook niet heel voor de hand liggend. Toch is het al langer bekend dat zelfs de gezondheid van je longen afhankelijk is van de voedingsstoffen die je binnenkrijgt. Daarom werd in deze thesis onderzoek gedaan naar de mogelijkheden om met voedingsinterventies “interstitiële” longziektes tegen te gaan.
Interstitiële longziektes zijn longziektes die het interstitium oftewel de ruimte tussen de longblaasjes en de bloedvaten aantasten. Het merendeel (65%) van dit type longziektes is idiopathisch, dit wil zeggen dat de oorzaak onbekend is. Het is dan ook lastig om hiervoor een doeltreffende geneesmiddelen te vinden. Bijgevolg hebben twee van de meest voorkomende interstitiële longziektes, IPF (idiopathische longfibrose) en sarcoïdose nog geen effectieve behandelmethodes. Zo heeft iemand met IPF slechts een mediane levensverwachting van 2 tot 5 jaar. Er zijn slechts twee medicijnen bekend die de ziekte kunnen afremmen, echter hebben deze medicijnen ook hun bijwerkingen en blijft de kwaliteit van leven achter. Sarcoïdose daarentegen verdwijnt na verloop van tijd in de meerderheid van de gevallen. In 30% van de gevallen blijft het echter aanhouden en  in 1-4% van de gevallen is het zelfs fataal.
Omdat behandelopties voor deze ziektes zo gelimiteerd zijn, terwijl de last voor de patiënten zo hoog is. Daarom is het van belang de ziekte op zoveel mogelijk manieren tegen te gaan.

Welke rol kan voeding spelen?
Ondanks het feit dat interstitiële longziektes een groot begrip is dat meerdere longziektes betreft, is het zo dat ze ook veel gemeen hebben. Zo zijn ontstekingen, oxidatieve stress en het risico op fibrose (littekenvorming) veel voorkomende verschijnselen bij deze ziektes Van verschillende voedingstoffen zoals antioxidanten is al bekend dat ze oxidatieve stress kunnen tegengaan. Ook hebben veel voedingsstoffen ontstekingsremmende effecten.
Er zijn al veel experimenten gebeurd met individuele voedingsstoffen en de invloed die ze uitoefenen op deze longziektes. Het merendeel van deze data is echter nog losstaand en gebaseerd op studies in het lab of op proefdieren. In dit onderzoek werd(en) al deze data samengelegd om een overzicht te creëren over welke voedingsstoffen nu positieve resultaten vertoonden. Op basis hiervan werd een dieet en een voedingsmiddel opgesteld waarmee mensen die lijden aan deze longziektes geholpen kunnen worden.

 

Welke voedingsstoffen zijn belangrijk

Een van de meest geteste voedingsstoffen is vitamine D, dat voorkomt in bjivoorbeeld vette vis. De associatie tussen tekorten aan vitamine D en het voorkomen van longziektes is al langer bekend Toch zijn hier ook risico’s aan verbonden. Zo zou vitamine D goed zijn in het voorkomen van IPF en sarcoïdose, maar indien de longziektes reeds aanwezig zijn kan het de situatie verergeren. Zo bleek dat het supplementeren van vitamine D aan muizen met fibrose cellulaire veroudering stimuleerden en werd bij patiënten met sarcoïdose een hoger risico op hypercalcemia en hypercalciuria gevonden indien vitamine D gecomplementeerd werd.
 Ook Vitamine K, een vitamine die voornamelijk voorkomt in groene groente kan een rol spelen. Deze voedingsstof is een klasse apart, vroeger dacht men immers dat longfibrose tegengegaan kon worden met vitamine K remmers zoals warfarine. Dit werd bijgevolg geruime tijd als medicatie gebruikt. Toen deze behandeling echter onderzocht werd vond men echter dat het de ziekte net verergerde. Sindsdien gaan er steeds meer stemmen op om ook te kijken naar de potentie van vitamine K om de ziekte tegen te gaan.
Verder is er melatonine, een hormoon voornamelijk bekend voor zijn rol in het slaapritme. Melatonine komt voor in bijvoorbeeld noten en kan verder opgewekt worden door andere voedingsstoffen. Van melatonine werd aangetoond dat het effectief wastegen oxidatieve stress, ontstekingen en fibrose in muizen met longfibrose. In sarcoïdose werd het ook reeds op mensen getest, hier zorgde het voor herstelling van het functioneren van de longen en het tegengaan van oxidatieve stress.
Ook Omega 3, een voedingstof aanwezig in bijvoorbeeld vette vis, toonde longfibrose bij muizen tegen te gaan door het remmen van oxidatieve stress, fibrose en ontsteking. Het werd echter nog niet getest bij mensen met longfibrose. Het is wel al eerder bewezen dat omega 3 ontstekingsremmend kan zijn bij mensen die lijden aan andere ontstekende longziektes.
Tot slot zijn zijn er nog de zogenaamde polyfenolen, dit zijn heel kleine voedingsstoffen. De meest getest polyfenolen zijn quercetine, resveratrol en curcumine. Ook deze waren in dierproeven actief tegen  ontsteking, oxidatieve stress en fibrose. Quercetine werd ook getest bij mensen met sarcoïdosis waar het oxidatieve stress tegen ging. Bovendien toonde resveratrol en quercetine in eerder onderzoek aan ontsteking tegen te gaan in andere ontstekende longziektes.

Hoe ziet het dieet/voedingsschema eruit.

Wat opvalt is dat de voorgestelde manier waarop deze voedingsstoffen werken nogal verschillen. Het zou dan ook kunnen dat de gecombineerde werking ervan nog extra effect geeft.
Daarom werd het volgende voedingsschema opgesteld. Het is een dieet voor een week waarbij voedingsstoffen in grote mate aanwezig zijn.

(afbeelding 1)

 

Ook werd er een smoothie ontwikkeld die rijk is aan de voedingsstoffen die een positieve werking blijken te hebben. Door de integratie van deze voedingsstoffen in een goede behandeling, zou het mogelijk zijn mensen beter te ondersteunen in hun ziekteproces. In de volgende afbeelding wordt een behandelproces gesuggereerd

(afbeelding 2)

 

De toekomst

Ook al is er al veel onderzoek verricht naar de effecten van voedingsstoffen, op interstitiële longziektes, toch blijft verder onderzoek  bij mensen van essentieel belang. Het is al langer geweten dat een gezond dieet bijdraagt tot een betere gezondheid. Daarom is het van belang om voeding en medicatie niet altijd strikt te scheiden. Zeker bij ernstige ziektes waarbij behandelopties gelimiteerd zijn is het nodig in te zetten op alle mogelijke  factoren waarmee de patiënt geholpen kan worden. Zo zou een integrale behandeling als IPF er als volgt uit kunnen zien.

(afbeelding 3)

Bibliografie

1. Panagiotou M, Polychronopoulos V, Strange C. Respiratory and lower limb muscle function in 
interstitial lung disease. Chron Respir Dis. 2016 May;13(2):162–72.  
2. Veltkamp M, Schimmelpennink MC. Behandeling met biologicals bij systeemziekten en ILD. 
Bijblijven. 2018 Apr 1;34(2):117–28.  
3. Wallis A, Spinks K. The diagnosis and management of interstitial lung diseases. BMJ. 2015 May 
7;350(may07 17):h2072–h2072.  
4. Bagnato G, Harari S. Cellular interactions in the pathogenesis of interstitial lung diseases. Eur 
Respir Rev. 2015 Mar 1;24(135):102–14.  
5. Verleden GM, Bois RM du, Bouros D, Drent M, Millar A, Müller‐Quernheim J, et al. Genetic 
predisposition and pathogenetic mechanisms of interstitial lung diseases of unknown origin. 
Eur Respir J. 2001 Jul 1;18(32 suppl):17S – 29s.  
6. Yang IV, Schwartz DA. Epigenetics of idiopathic pulmonary fibrosis. Transl Res. 2015 Jan 
1;165(1):48–60.  
7. Yang IV, Fingerlin TE, Evans CM, Schwarz MI, Schwartz DA. MUC5B and Idiopathic Pulmonary 
Fibrosis. Ann Am Thorac Soc. 2015 Nov;12(Suppl 2):S193–9.  
8. Walsh SLF, Hansell DM. Diffuse interstitial lung disease: overlaps and uncertainties. Eur Radiol. 
2010 Aug 1;20(8):1859–67.  
9. Duchemann B, Annesi‐Maesano I, Naurois CJ de, Sanyal S, Brillet P‐Y, Brauner M, et al. 
Prevalence and incidence of interstitial lung diseases in a multi‐ethnic county of Greater Paris. 
Eur Respir J. 2017 Aug 1;50(2):1602419.  
10. Kreuter M, Herth FJF, Wacker M, Leidl R, Hellmann A, Pfeifer M, et al. Exploring Clinical and 
Epidemiological Characteristics of Interstitial Lung Diseases: Rationale, Aims, and Design of a 
Nationwide Prospective Registry—The EXCITING‐ILD Registry [Internet]. BioMed Research 
International. 2015 [cited 2019 Jan 10]. Available from: 
https://www.hindawi.com/journals/bmri/2015/123876/ 
11. Interstitial lung diseases ‐ ERS [Internet]. [cited 2018 Dec 29]. Available from: 
https://www.erswhitebook.org/chapters/interstitial‐lung‐diseases/ 
12. Gulati M. Diagnostic assessment of patients with interstitial lung disease. Prim Care Respir J. 
2011;20(2):120.  
13. Karakatsani A, Papakosta D, Rapti A, Antoniou KM, Dimadi M, Markopoulou A, et al. 
Epidemiology of interstitial lung diseases in Greece. Respir Med. 2009 Aug 1;103(8):1122–9.  
14. The British Thoracic Society Interstitial Lung Disease Registry Programme [Internet]. British 
Thorac Society; 2016 [cited 2019 Jan 10] p. 20. (Annual report). Report No.: 3. Available from: 
https://www.brit‐thoracic.org.uk/document‐library/audit‐and‐quality‐improvement/lung‐
disease‐registry/bts‐ild‐registry‐annual‐report‐201516/ 
15. Interstitial lung disease [Internet]. European Lung Foundation ‐ ELF. [cited 2018 Dec 29]. 
Available from: https://www.europeanlung.org/en/lung‐disease‐and‐information/lung‐
diseases/interstitial‐lung‐disease 
16. Pulmonary sarcoidosis‐ ClinicalKey [Internet]. [cited 2019 Jan 21]. Available from: 
https://www‐clinicalkey‐com.ezproxy.ub.unimaas.nl/#!/content/playContent/1‐s2.0‐
S221326001830064X 
17. Gerke AK. Morbidity and mortality in sarcoidosis. Curr Opin Pulm Med. 2014 Sep;20(5):472–8. 
18. Lee AS, Mira‐Avendano I, Ryu JH, Daniels CE. The burden of idiopathic pulmonary fibrosis: an 
unmet public health need. Respir Med. 2014 Jul;108(7):955–67.  
19. Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. The Lancet. 
2017;389(10082):1941–1952.  
20. Selman M, King TE, Pardo A. Idiopathic Pulmonary Fibrosis: Prevailing and Evolving 
Hypotheses about Its Pathogenesis and Implications for Therapy. Ann Intern Med. 2001 Jan 
16;134(2):136.  

 

 

40 

 

21. Vancheri C. Common pathways in idiopathic pulmonary fibrosis and cancer. Eur Respir Rev. 
2013 Sep 1;22(129):265–72.  
22. Sgalla G, Iovene B, Calvello M, Ori M, Varone F, Richeldi L. Idiopathic pulmonary fibrosis: 
pathogenesis and management. Respir Res [Internet]. 2018 [cited 2019 Jan 20];19. Available 
from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824456/ 
23. Todd NW, Atamas SP, Luzina IG, Galvin JR. Permanent alveolar collapse is the predominant 
mechanism in idiopathic pulmonary fibrosis. Expert Rev Respir Med. 2015 Jul 4;9(4):411–8.  
24. Hosseinzadeh A, Javad‐Moosavi SA, Reiter RJ, Hemati K, Ghaznavi H, Mehrzadi S. Idiopathic 
pulmonary fibrosis (IPF) signaling pathways and protective roles of melatonin. Life Sci. 2018 
May 15;201:17–29.  
25. Wollin L, Wex E, Pautsch A, Schnapp G, Hostettler KE, Stowasser S, et al. Mode of action of 
nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur Respir J. 2015;45(5):1434–
1445.  
26. Meyer K, Nathan S. Idiopathic Pulmonary Fibrosis: A Comprehensive Clincical Guide. second. 
Vol. Past Therapies in IPF. 2019. 475 p.  
27. Network IPFCR. Prednisone, azathioprine, and N‐acetylcysteine for pulmonary fibrosis. N Engl 
J Med. 2012;366(21):1968–1977.  
28. George TJ, Arnaoutakis GJ, Shah AS. Lung transplant in idiopathic pulmonary fibrosis. Arch 
Surg. 2011;146(10):1204–1209.  
29. Thabut G, Mal H. Outcomes after lung transplantation. J Thorac Dis. 2017 Aug;9(8):2684–91. 
30. Verleden GM, Dupont L, Yserbyt J, Schaevers V, Van Raemdonck D, Neyrinck A, et al. Recipient 
selection process and listing for lung transplantation. J Thorac Dis. 2017 Sep;9(9):3372–84.  
31. Raghu G, Rochwerg B, Zhang Y, Garcia CAC, Azuma A, Behr J, et al. An Official 
ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An 
Update of the 2011 Clinical Practice Guideline. Am J Respir Crit Care Med. 2015 Jul 
15;192(2):e3–19.  
32. Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, et al. Pirfenidone in 
patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. The Lancet. 
2011;377(9779):1760–1769.  
33. Collard HR, Richeldi L. Interstitial Lung Disease. Vol. The advent of pirfenidone. 2018. 190 p. 
34. Hilberg O, Simonsen U, Bois R du, Bendstrup E. Pirfenidone: significant treatment effects in 
idiopathic pulmonary fibrosis. Clin Respir J. 2012;6(3):131–43.  
35. Case AH, Johnson P. Clinical use of nintedanib in patients with idiopathic pulmonary fibrosis. 
BMJ Open Respir Res. 2017 Jun 1;4(1):e000192.  
36. Roth GJ, Binder R, Colbatzky F, Dallinger C, Schlenker‐Herceg R, Hilberg F, et al. Nintedanib: 
From Discovery to the Clinic. J Med Chem. 2015 Feb 12;58(3):1053–63.  
37. Flaherty KR, Fell CD, Huggins JT, Nunes H, Sussman R, Valenzuela C, et al. Safety of nintedanib 
added to pirfenidone treatment for idiopathic pulmonary fibrosis. Eur Respir J. 2018 Aug 
1;52(2):1800230.  
38. Vancheri C, Kreuter M, Richeldi L, Ryerson CJ, Valeyre D, Grutters JC, et al. Nintedanib with 
Add‐on Pirfenidone in Idiopathic Pulmonary Fibrosis. Results of the INJOURNEY Trial. Am J 
Respir Crit Care Med. 2017 Sep 10;197(3):356–63.  
39. Lehtonen ST, Veijola A, Karvonen H, Lappi‐Blanco E, Sormunen R, Korpela S, et al. Pirfenidone 
and nintedanib modulate properties of fibroblasts and myofibroblasts in idiopathic pulmonary 
fibrosis. Respir Res. 2016 Feb 4;17:14.  
40. Chen ES, Moller DR. Etiologies of Sarcoidosis. Clin Rev Allergy Immunol. 2015 Aug 1;49(1):6–
18.  
41. Kreider ME, Christie JD, Thompson B, Newman L, Rose C, Barnard J, et al. Relationship of 
Environmental Exposures to the Clinical Phenotype of Sarcoidosis. Chest. 2005 Jul 
1;128(1):207–15.  

 

 

41 

 

42. Rossman MD, Thompson B, Frederick M, Maliarik M, Iannuzzi MC, Rybicki BA, et al. HLA‐
DRB1*1101: A Significant Risk Factor for Sarcoidosis in Blacks and Whites. Am J Hum Genet. 
2003 Oct;73(4):720–35.  
43. Statement on Sarcoidosis. Am J Respir Crit Care Med. 1999 Aug 1;160(2):736–55. 
44. Baughman RP, Culver DA, Judson MA. A Concise Review of Pulmonary Sarcoidosis. Am J Respir 
Crit Care Med. 2011 Mar 1;183(5):573–81.  
45. Lynch JP, Ma YL, Koss MN, White ES. Pulmonary sarcoidosis. In: Seminars in respiratory and 
critical care medicine. Copyright\copyright 2007 by Thieme Medical Publishers, Inc., 333 
Seventh Avenue, New …; 2007. p. 053–074.  
46. Broos CE, van Nimwegen M, Hoogsteden HC, Hendriks RW, Kool M, van den Blink B. 
Granuloma Formation in Pulmonary Sarcoidosis. Front Immunol [Internet]. 2013 Dec 10 [cited 
2019 Feb 28];4. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3857538/ 
47. Patterson KC, Chen ES. The Pathogenesis of Pulmonary Sarcoidosis and Implications for 
Treatment. Chest. 2018 Jun 1;153(6):1432–42.  
48. Vecchiarelli A, Dottorini M, Pietrella D, Monari C, Retini C, Todisco T, et al. Role of human 
alveolar macrophages as antigen‐presenting cells in Cryptococcus neoformans infection. Am J 
Respir Cell Mol Biol. 1994 Aug;11(2):130–7.  
49. Zaba LC, Smith GP, Sanchez M, Prystowsky SD. Dendritic Cells in the Pathogenesis of 
Sarcoidosis. Am J Respir Cell Mol Biol. 2010 Jan;42(1):32–9.  
50. Miedema JR, Kaiser Y, Broos CE, Wijsenbeek MS, Grunewald J, Kool M. Th17‐lineage cells in 
pulmonary sarcoidosis and Löfgren’s syndrome: Friend or foe? J Autoimmun. 2018 Feb 
1;87:82–96.  
51. Silva E, Souchelnytskyi S, Kasuga K, Eklund A, Grunewald J, Wheelock ÅM. Quantitative intact 
proteomics investigations of alveolar macrophages in sarcoidosis. Eur Respir J. 2013 Jun 
1;41(6):1331–9.  
52. Herbert C, Ahmadzai H, Thomas PS. Chapter 8 ‐ Proinflammatory and Regulatory Cytokines in 
Sarcoidosis. In: Foti M, Locati M, editors. Cytokine Effector Functions in Tissues [Internet]. 
Academic Press; 2017 [cited 2019 Mar 27]. p. 129–38. Available from: 
http://www.sciencedirect.com/science/article/pii/B9780128042144000075 
53. Ringkowski S, Thomas PS, Herbert C. Interleukin‐12 family cytokines and sarcoidosis. Front 
Pharmacol. 2014;5:233.  
54. Herbert C, Ahmadzai H, Thomas PS. Proinflammatory and Regulatory Cytokines in Sarcoidosis. 
In: Cytokine Effector Functions in Tissues. Elsevier; 2017. p. 129–138.  
55. Judson MA, Boan AD, Lackland DT. The clinical course of sarcoidosis: presentation, diagnosis, 
and treatment in a large white and black cohort in the United States. Sarcoidosis Vasc Diffuse 
Lung Dis. 2012 Dec 1;29(2):119–27.  
56. Beegle SH, Barba K, Gobunsuy R, Judson MA. Current and emerging pharmacological 
treatments for sarcoidosis: a review. Drug Des Devel Ther. 2013 Apr 12;7:325–38.  
57. Grutters JC, Bosch JMM van den. Corticosteroid treatment in sarcoidosis. Eur Respir J. 2006 
Sep 1;28(3):627–36.  
58. American Thorac Society. Treatment of Sarcoidosis [Internet]. 2018 p. 9–10. (Am J Respir Crit 
Care Med Vol. 197). Available from: https://www.thoracic.org/patients/patient
resources/resources/sarcoidosis‐pt‐2‐treatment.pdf 
59. Walda IC, Tabak C, Smit HA, Räsänen L, Fidanza F, Menotti A, et al. Diet and 20‐year chronic 
obstructive pulmonary disease mortality in middle‐aged men from three European countries. 
Eur J Clin Nutr. 2002;56(7):638.  
60. Tabak C, Smit HA, Heederik D, Ocke MC, Kromhout D. Diet and chronic obstructive pulmonary 
disease: independent beneficial effects of fruits, whole grains, and alcohol (the MORGEN 
study). Clin Exp Allergy. 2001;31(5):747–755.  
61. The role of vitamin D in pulmonary disease: COPD, asthma, infection, and cancer | Respiratory 
Research | Full Text [Internet]. [cited 2019 Feb 2]. Available from: https://respiratory
research.biomedcentral.com/articles/10.1186/1465‐9921‐12‐31 

 

 

42 

 

62. Miyake Y. Case‐Control Study of Idiopathic Pulmonary Fibrosis in Japan. In: Washio M, Kobashi 
G, editors. Epidemiological Studies of Specified Rare and Intractable Disease [Internet]. 
Singapore: Springer Singapore; 2019 [cited 2019 Jan 23]. p. 103–16. (Current Topics in 
Environmental Health and Preventive Medicine). Available from: https://doi.org/10.1007/978
981‐13‐1096‐6_7 
63. Miyake Y, Sasaki S, Yokoyama T, Chida K, Azuma A, Suda T, et al. Vegetable, Fruit, and Cereal 
Intake and Risk of Idiopathic Pulmonary Fibrosis in Japan. Ann Nutr Metab. 2004;48(6):390–7.  
64. de Boer A, van de Worp WRPH, Hageman GJ, Bast A. The effect of dietary components on 
inflammatory lung diseases – a literature review. Int J Food Sci Nutr. 2017 Oct 3;68(7):771–87.  
65. Greiffo FR, Eickelberg O, Fernandez IE. Systems medicine advances in interstitial lung disease. 
Eur Respir Rev. 2017 Sep 30;26(145):170021.  
66. R Core Team. R: A language and environment for statistical computing. R Foundation for 
Statistical Computing, Vienna, Austria. [Internet]. Available from: https://www.R‐project.org/ 
67. Calcagno V, Mazancourt C de. glmulti: An R Package for Easy Automated Model Selection with 
(Generalized) Linear Models. J Stat Softw. 2010 May 31;34(1):1–29.  
68. Factors that influence the cutaneous synthesis and dietary sources of vitamin D ‐ 
ScienceDirect [Internet]. [cited 2019 Jan 29]. Available from: https://www‐sciencedirect‐
com.ezproxy.ub.unimaas.nl/science/article/pii/S000398610600508X 
69. Finklea JD, Grossmann RE, Tangpricha V. Vitamin D and Chronic Lung Disease: A Review of 
Molecular Mechanisms and Clinical Studies. Adv Nutr. 2011 May 1;2(3):244–53.  
70. Vitamin D and respiratory health ‐ Hughes ‐ 2009 ‐ Clinical & Experimental Immunology ‐ 
Wiley Online Library [Internet]. [cited 2019 Jan 29]. Available from: https://onlinelibrary
wiley‐com.ezproxy.ub.unimaas.nl/doi/full/10.1111/j.1365‐2249.2009.04001.x 
71. Xie Z, He Y, Sun Y, Lin Z, Yang M, Liu Q, et al. Association between pulmonary fibrosis and 
osteoporosis in the elderly people: A case‐control study. Medicine (Baltimore). 2016 
Nov;95(44):e5239.  
72. al CC et. Idiopathic pulmonary fibrosis a rare disease with severe bone fragility. ‐ PubMed ‐ 
NCBI [Internet]. [cited 2019 Jan 24]. Available from: 
https://www.ncbi.nlm.nih.gov/pubmed/27393142 
73. Alhamad EH, Nadama R. Bone mineral density in patients with interstitial lung disease. 
Sarcoidosis Vasc Diffuse Lung Dis Off J WASOG. 2015 Jul 22;32(2):151–9.  
74. Olson AL, Swigris JJ, Raghu G, Brown KK. Seasonal variation: mortality from pulmonary fibrosis 
is greatest in the winter. Chest. 2009 Jul;136(1):16–22.  
75. Shi Y, Liu T, Yao L, Xing Y, Zhao X, Fu J, et al. Chronic vitamin D deficiency induces lung fibrosis 
through activation of the renin‐angiotensin system. Sci Rep. 2017 Jun 12;7(1):3312.  
76. Tzilas V, Bouros E, Barbayianni I, Karampitsakos T, Kourtidou S, Ntassiou M, et al. Vitamin D 
prevents experimental lung fibrosis and predicts survival in patients with idiopathic pulmonary 
fibrosis. Pulm Pharmacol Ther. 2019 Jan 16;  
77. Zhang Z, Yu X, Fang X, Liang A, Yu Z, Gu P, et al. Preventive effects of vitamin D treatment on 
bleomycin‐induced pulmonary fibrosis. Sci Rep. 2015 Dec 2;5:17638.  
78. Tan Z‐X, Chen Y‐H, Xu S, Qin H‐Y, Zhang C, Zhao H, et al. Calcitriol inhibits bleomycin‐induced 
early pulmonary inflammatory response and epithelial‐mesenchymal transition in mice. 
Toxicol Lett. 2016 Jan 5;240(1):161–71.  
79. Jiang F, Yang Y, Xue L, Li B, Zhang Z. 1α,25‐dihydroxyvitamin D3 Attenuates TGF‐β‐Induced 
Pro‐Fibrotic Effects in Human Lung Epithelial Cells through Inhibition of Epithelial–
Mesenchymal Transition. Nutrients [Internet]. 2017 Sep [cited 2019 Jan 24];9(9). Available 
from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622740/ 
80. Ramirez AM, Wongtrakool C, Welch T, Steinmeyer A, Zügel U, Roman J. Vitamin D inhibition of 
pro‐fibrotic effects of transforming growth factor beta1 in lung fibroblasts and epithelial cells. 
J Steroid Biochem Mol Biol. 2010 Feb 15;118(3):142–50.  

 

 

43 

 

81. Guijarro T, Magro‐Lopez E, Manso J, Garcia‐Martinez R, Fernandez‐Aceñero MJ, Liste I, et al. 
Detrimental pro‐senescence effects of vitamin D on lung fibrosis. Mol Med Camb Mass. 2018 
19;24(1):64.  
82. Dietary Intake and Adequacy of Vitamin K | The Journal of Nutrition | Oxford Academic 
[Internet]. [cited 2019 Jan 29]. Available from: 
https://academic.oup.com/jn/article/128/5/785/4722398 
83. De Brouwer B, Piscaer I, Von Der Thusen JH, Grutters JC, Schutgens RE, Wouters EF, et al. 
Should vitamin K be supplemented instead of antagonised in patients with idiopathic 
pulmonary fibrosis? Expert Rev Respir Med. 2018;12(3):169–75.  
84. de Brouwer B, White E s., Janssen R. Low Vitamin K Status in Idiopathic Pulmonary Fibrosis. In: 
A43 ILD SCIENTIFIC ABSTRACTS: GENERAL [Internet]. American Thoracic Society; 2018 [cited 
2019 Jan 24]. p. A1698–A1698. (American Thoracic Society International Conference 
Abstracts). Available from: https://www.atsjournals.org/doi/abs/10.1164/ajrccm
conference.2018.197.1_MeetingAbstracts.A1698 
85. Drent M, Wijnen P, Bast A. Pharmacogenetic variants and vitamin K deficiency: a risk factor or 
trigger for fibrosing interstitial pneumonias? Curr Opin Pulm Med. 2018;24(3):287–95.  
86. Wijnen PA, Linssen CF, Haenen GR, Bekers O, Drent M. Variant VKORC1 and CYP2C9 Alleles in 
Patients with Diffuse Alveolar Hemorrhage Caused by Oral Anticoagulants. Mol Diagn Ther. 
2010 Feb 1;14(1):23–30.  
87. Noth I, Anstrom KJ, Calvert SB, de Andrade J, Flaherty KR, Glazer C, et al. A placebo‐controlled 
randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2012 
Jul 1;186(1):88–95.  
88. The effect of anticoagulant therapy for idiopathic pulmonary fibrosis in real life practice | 
Sarcoidosis vasculitis and diffuse lung disease [Internet]. [cited 2019 Jan 29]. Available from: 
http://mattioli1885journals.com/index.php/sarcoidosis/article/view/3023 
89. Kreuter M, Wijsenbeek MS, Vasakova M, Spagnolo P, Kolb M, Costabel U, et al. Unfavourable 
effects of medically indicated oral anticoagulants on survival in idiopathic pulmonary fibrosis. 
Eur Respir J. 2016;47(6):1776–84.  
90. Lin C, von der Thüsen J, van der Poll T, Borensztajn K, Spek CA. Increased Mortality during 
Bleomycin‐induced Pulmonary Fibrosis due to Low Endogenous Activated Protein C Levels. Am 
J Respir Crit Care Med. 2015 Nov 15;192(10):1257–9.  
91. Kubo H, Nakayama K, Yanai M, Suzuki T, Yamaya M, Watanabe M, et al. Anticoagulant Therapy 
for Idiopathic Pulmonary Fibrosis. Chest. 2005 Sep 1;128(3):1475–82.  
92. Meng X, Li Y, Li S, Zhou Y, Gan R‐Y, Xu D‐P, et al. Dietary Sources and Bioactivities of 
Melatonin. Nutrients [Internet]. 2017 Apr 7 [cited 2019 Jan 25];9(4). Available from: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409706/ 
93. Hosseinzadeh A, Javad‐Moosavi SA, Reiter RJ, Yarahmadi R, Ghaznavi H, Mehrzadi S. 
Oxidative/nitrosative stress, autophagy and apoptosis as therapeutic targets of melatonin in 
idiopathic pulmonary fibrosis. Expert Opin Ther Targets. 2018 Dec 2;22(12):1049–61.  
94. Zhao X, Sun J, Su W, Shan H, Zhang B, Wang Y, et al. Melatonin Protects against Lung Fibrosis 
by Regulating the Hippo/YAP Pathway. Int J Mol Sci. 2018 Apr 9;19(4).  
95. Arslan SO, Zerin M, Vural H, Coskun A. The effect of melatonin on bleomycin‐induced 
pulmonary fibrosis in rats. J Pineal Res. 2002 Jan;32(1):21–5.  
96. Karimfar MH, Rostami S, Haghani K, Bakhtiyari S, Noori‐Zadeh A. MELATONIN ALLEVIATES 
BLEOMYCIN‐INDUCED PULMONARY FIBROSIS IN MICE. J Biol Regul Homeost Agents. 2015 
Jun;29(2):327–34.  
97. Yildirim Z, Kotuk M, Erdogan H, Iraz M, Yagmurca M, Kuku I, et al. Preventive effect of 
melatonin on bleomycin‐induced lung fibrosis in rats. J Pineal Res. 2006 Jan;40(1):27–33.  
98. Genovese T, Di Paola R, Mazzon E, Muià C, Caputi AP, Cuzzocrea S. Melatonin limits lung injury 
in bleomycin treated mice. J Pineal Res. 2005 Sep;39(2):105–12.  

 

 

44 

 

99. Zhao H, Wu Q‐Q, Cao L‐F, Qing H‐Y, Zhang C, Chen Y‐H, et al. Melatonin inhibits endoplasmic 
reticulum stress and epithelial‐mesenchymal transition during bleomycin‐induced pulmonary 
fibrosis in mice. PloS One. 2014;9(5):e97266.  
100. Yu N, Sun Y‐T, Su X‐M, He M, Dai B, Kang J. Melatonin attenuates TGFβ1‐induced epithelial‐
mesenchymal transition in lung alveolar epithelial cells. Mol Med Rep. 2016 Dec;14(6):5567–
72.  
101. Wall R, Ross RP, Fitzgerald GF, Stanton C. Fatty acids from fish: the anti‐inflammatory 
potential of long‐chain omega‐3 fatty acids. Nutr Rev. 2010 May 1;68(5):280–9.  
102. Simopoulos AP. Omega‐3 fatty acids in health and disease and in growth and development. 
Am J Clin Nutr. 1991 Sep 1;54(3):438–63.  
103. Chen J, Zeng T, Zhao X, Xiea K, Bi Y, Zhong Z, et al. Docosahexaenoic acid (DHA) ameliorates 
paraquat‐induced pulmonary fibrosis in rats possibly through up‐regulation of Smad 7 and 
SnoN. Food Chem Toxicol Int J Publ Br Ind Biol Res Assoc. 2013 Jul;57:330–7.  
104. Zhao H, Chan‐Li Y, Collins SL, Zhang Y, Hallowell RW, Mitzner W, et al. Pulmonary delivery of 
docosahexaenoic acid mitigates bleomycin‐induced pulmonary fibrosis. BMC Pulm Med. 2014 
Apr 18;14:64.  
105. Velten M, Britt RD, Heyob KM, Tipple TE, Rogers LK. Maternal dietary docosahexaenoic acid 
supplementation attenuates fetal growth restriction and enhances pulmonary function in a 
newborn mouse model of perinatal inflammation. J Nutr. 2014 Mar;144(3):258–66.  
106. Ziboh VA, Yun M, Hyde DM, Giri SN. gamma‐Linolenic acid‐containing diet attenuates 
bleomycin‐induced lung fibrosis in hamsters. Lipids. 1997 Jul;32(7):759–67.  
107. Lawrenz J, Herndon B, Kamal A, Mehrer A, Dim DC, Baidoo C, et al. Dietary Flaxseed Oil 
Protects against Bleomycin‐Induced Pulmonary Fibrosis in Rats. Pulm Med. 
2012;2012:457031.  
108. Serhan CN, Chiang N, Dalli J, Levy BD. Lipid Mediators in the Resolution of Inflammation. Cold 
Spring Harb Perspect Biol [Internet]. 2015 Feb [cited 2019 Feb 4];7(2). Available from: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315926/ 
109. Yatomi M, Hisada T, Ishizuka T, Koga Y, Ono A, Kamide Y, et al. 17(R)‐resolvin D1 ameliorates 
bleomycin‐induced pulmonary fibrosis in mice. Physiol Rep. 2015 Dec;3(12).  
110. Li H, Hao Y, Zhang H, Ying W, Li D, Ge Y, et al. Posttreatment with Protectin DX ameliorates 
bleomycin‐induced pulmonary fibrosis and lung dysfunction in mice. Sci Rep. 2017 May 
3;7:46754.  
111. Pounis G, Arcari A, Costanzo S, Di Castelnuovo A, Bonaccio M, Persichillo M, et al. Favorable 
association of polyphenol‐rich diets with lung function: Cross‐sectional findings from the Moli‐
sani study. Respir Med. 2018;136:48–57.  
112. Lee JC, Kinniry PA, Arguiri E, Serota M, Kanterakis S, Chatterjee S, et al. Dietary curcumin 
increases antioxidant defenses in lung, ameliorates radiation‐induced pulmonary fibrosis, and 
improves survival in mice. Radiat Res. 2010 May;173(5):590–601.  
113. Hu Y, Li M, Zhang M, Jin Y. Treatment of idiopathic pulmonary fibrosis with curcumin large 
porous microparticles. Int J Pharm. 2018 Nov 15;551(1–2):212–22.  
114. Punithavathi D, Venkatesan N, Babu M. Protective effects of curcumin against amiodarone‐
induced pulmonary fibrosis in rats. Br J Pharmacol. 2003 Aug;139(7):1342–50.  
115. Hamdy MA, El‐Maraghy SA, Kortam MAEA. Modulatory Effects of Curcumin and Green Tea 
Extract against Experimentally Induced Pulmonary Fibrosis: A Comparison with N‐Acetyl 
Cysteine. J Biochem Mol Toxicol. 2012;26(11):461–8.  
116. Cho YJ, Yi CO, Jeon BT, Jeong YY, Kang GM, Lee JE, et al. Curcumin attenuates radiation‐
induced inflammation and fibrosis in rat lungs. Korean J Physiol Pharmacol Off J Korean 
Physiol Soc Korean Soc Pharmacol. 2013 Aug;17(4):267–74.  
117. Smith MR, Gangireddy SR, Narala VR, Hogaboam CM, Standiford TJ, Christensen PJ, et al. 
Curcumin inhibits fibrosis‐related effects in IPF fibroblasts and in mice following bleomycin‐
induced lung injury. Am J Physiol Lung Cell Mol Physiol. 2010 May;298(5):L616‐625.  

 

 

45 

 

118. Zhang D, Huang C, Yang C, Liu RJ, Wang J, Niu J, et al. Antifibrotic effects of curcumin are 
associated with overexpression of cathepsins K and L in bleomycin treated mice and human 
fibroblasts. Respir Res. 2011 Nov 29;12:154.  
119. Saidi A, Kasabova M, Vanderlynden L, Wartenberg M, Kara‐Ali GH, Marc D, et al. Curcumin 
inhibits the TGF‐β1‐dependent differentiation of lung fibroblasts via PPARγ‐driven 
upregulation of cathepsins B and L. Sci Rep. 2019 Jan 24;9(1):491.  
120. Liu D, Gong L, Zhu H, Pu S, Wu Y, Zhang W, et al. Curcumin Inhibits Transforming Growth 
Factor β Induced Differentiation of Mouse Lung Fibroblasts to Myofibroblasts. Front 
Pharmacol. 2016;7:419.  
121. Gaedeke J, Noble NA, Border WA. Curcumin blocks multiple sites of the TGF‐beta signaling 
cascade in renal cells. Kidney Int. 2004 Jul;66(1):112–20.  
122. Frémont L. Biological effects of resveratrol. Life Sci. 2000 Jan 14;66(8):663–73. 
123. Gharaee‐Kermani M, Moore BB, Macoska JA. Resveratrol‐Mediated Repression and Reversion 
of Prostatic Myofibroblast Phenoconversion. PloS One. 2016;11(7):e0158357.  
124. Fagone E, Conte E, Gili E, Fruciano M, Pistorio MP, Lo Furno D, et al. Resveratrol inhibits 
transforming growth factor‐β–induced proliferation and differentiation of ex vivo human lung 
fibroblasts into myofibroblasts through ERK/Akt inhibition and PTEN restoration. Exp Lung 
Res. 2011;37(3):162–174.  
125. He X, Wang L, Szklarz G, Bi Y, Ma Q. Resveratrol inhibits paraquat‐induced oxidative stress and 
fibrogenic response by activating the nuclear factor erythroid 2‐related factor 2 pathway. J 
Pharmacol Exp Ther. 2012;342(1):81–90.  
126. Şener G, Topaloğlu N, Şehirli AÖ, Ercan F, Gedik N. Resveratrol alleviates bleomycin‐induced 
lung injury in rats. Pulm Pharmacol Ther. 2007;20(6):642–649.  
127. Rong L, Wu J, Wang W, Zhao R‐P, Xu X‐W, Hu D. Sirt 1 activator attenuates the bleomycin‐
induced lung fibrosis in mice via inhibiting epithelial‐to‐mesenchymal transition (EMT). Eur 
Rev Med Pharmacol Sci. 2016;20(10):2144–50.  
128. Chu H, Jiang S, Liu Q, Ma Y, Zhu X, Liang M, et al. Sirtuin1 Protects against Systemic Sclerosis‐
related Pulmonary Fibrosis by Decreasing Proinflammatory and Profibrotic Processes. Am J 
Respir Cell Mol Biol. 2018;58(1):28–39.  
129. Sosulski ML, Gongora R, Feghali‐Bostwick C, Lasky JA, Sanchez CG. Sirtuin 3 Deregulation 
Promotes Pulmonary Fibrosis. J Gerontol A Biol Sci Med Sci. 2017 May 1;72(5):595–602.  
130. Akgedik R, Akgedik Ş, Karamanlı H, Uysal S, Bozkurt B, Ozol D, et al. Effect of resveratrol on 
treatment of bleomycin‐induced pulmonary fibrosis in rats. Inflammation. 2012;35(5):1732–
1741.  
131. Zeng Z, Cheng S, Chen H, Li Q, Hu Y, Wang Q, et al. Activation and overexpression of Sirt1 
attenuates lung fibrosis via P300. Biochem Biophys Res Commun. 2017 13;486(4):1021–6.  
132. Li J, Liang C, Zhang Z‐K, Pan X, Peng S, Lee W‐S, et al. TAK1 inhibition attenuates both 
inflammation and fibrosis in experimental pneumoconiosis. Cell Discov. 2017;3:17023.  
133. Impellizzeri D, Talero E, Siracusa R, Alcaide A, Cordaro M, Maria Zubelia J, et al. Protective 
effect of polyphenols in an inflammatory process associated with experimental pulmonary 
fibrosis in mice. Br J Nutr. 2015 Sep 28;114(6):853–65.  
134. al SG et. Resveratrol alleviates bleomycin‐induced lung injury in rats. ‐ PubMed ‐ NCBI 
[Internet]. [cited 2019 Jan 30]. Available from: 
https://www.ncbi.nlm.nih.gov/pubmed/17035056 
135. Formica JV, Regelson W. Review of the biology of quercetin and related bioflavonoids. Food 
Chem Toxicol. 1995;33(12):1061–1080.  
136. Boots AW, Haenen GR, Bast A. Health effects of quercetin: from antioxidant to nutraceutical. 
Eur J Pharmacol. 2008;585(2–3):325–337.  
137. Nakamura T, Matsushima M, Hayashi Y, Shibasaki M, Imaizumi K, Hashimoto N, et al. 
Attenuation of transforming growth factor‐β‐stimulated collagen production in fibroblasts by 
quercetin‐induced heme oxygenase‐1. Am J Respir Cell Mol Biol. 2011 May;44(5):614–20.  

 

 

46 

 

138. Veith C, Drent M, Bast A, van Schooten FJ, Boots AW. The disturbed redox‐balance in 
pulmonary fibrosis is modulated by the plant flavonoid quercetin. Toxicol Appl Pharmacol. 
2017 Dec 1;336:40–8.  
139. Baowen Q, Yulin Z, Xin W, Wenjing X, Hao Z, Zhizhi C, et al. A further investigation concerning 
correlation between anti‐fibrotic effect of liposomal quercetin and inflammatory cytokines in 
pulmonary fibrosis. Eur J Pharmacol. 2010 Sep 10;642(1–3):134–9.  
140. Taslidere E, Esrefoglu M, Elbe H, Cetin A, Ates B. Protective effects of melatonin and quercetin 
on experimental lung injury induced by carbon tetrachloride in rats. Exp Lung Res. 2014 
Mar;40(2):59–65.  
141. Verma R, Kushwah L, Gohel D, Patel M, Marvania T, Balakrishnan S. Evaluating the 
Ameliorative Potential of Quercetin against the Bleomycin‐Induced Pulmonary Fibrosis in 
Wistar Rats. Pulm Med. 2013;2013:921724.  
142. Boadi WY, Johnson D. Effects of low doses of quercetin and genistein on oxidation and 
carbonylation in hemoglobin and myoglobin. J Diet Suppl. 2014 Sep;11(3):272–87.  
143. al VC et. The disturbed redox‐balance in pulmonary fibrosis is modulated by the plant 
flavonoid quercetin. ‐ PubMed ‐ NCBI [Internet]. [cited 2019 Jan 30]. Available from: 
https://www.ncbi.nlm.nih.gov/pubmed/28987380 
144. Hohmann MS, Habiel DM, Coelho AL, Verri WA, Hogaboam CM. Quercetin Enhances Ligand‐
induced Apoptosis in Senescent Idiopathic Pulmonary Fibrosis Fibroblasts and Reduces Lung 
Fibrosis In Vivo. Am J Respir Cell Mol Biol. 2019 Jan;60(1):28–40.  
145. Baughman RP, Papanikolaou I. Current concepts regarding calcium metabolism and bone 
health in sarcoidosis. Curr Opin Pulm Med. 2017;23(5):476–481.  
146. Sharma OP. Vitamin D and sarcoidosis. Curr Opin Pulm Med. 2010;16(5):487–488. 
147. Kiani A, Abedini A, Adcock IM, Mirenayat MS, Taghavi K, Mortaz E, et al. Association Between 
Vitamin D Deficiencies in Sarcoidosis with Disease Activity, Course of Disease and Stages of 
Lung Involvements. J Med Biochem. 2018 Apr 1;37(2):103–9.  
148. Burke RR, Rybicki BA, Rao DS. Calcium and Vitamin D in Sarcoidosis: How to Assess and 
Manage. Semin Respir Crit Care Med. 2010 Aug;31(4):474–84.  
149. Sharma OP. Vitamin D, Calcium, and Sarcoidosis. Chest. 1996 Feb 1;109(2):535–9. 
150. Baughman RP, Lower EE. Goldilocks, vitamin D and sarcoidosis. Arthritis Res Ther. 2014 May 
23;16(3):111.  
151. Watts RA, Scott DGI. Landmark Papers in Rheumatology. Oxford University Press; 2015. 379 p. 
152. Capolongo G, Xu LHR, Accardo M, Sanduzzi A, Stanziola AA, Colao A, et al. Vitamin‐D status 
and mineral metabolism in two ethnic populations with sarcoidosis. J Investig Med Off Publ 
Am Fed Clin Res. 2016 Jun;64(5):1025–34.  
153. Filipovic S, Violeta V, Jelica V, Mihailo S, Aleksandar J. Vitamin D deficiency and activity of 
sarcoidosis. Eur Respir J. 2016 Sep 1;48(suppl 60):PA827.  
154. Kamphuis LS, Bonte‐Mineur F, Laar JA van, Hagen PM van, Daele PL van. Calcium and Vitamin 
D in Sarcoidosis: Is Supplementation Safe? J Bone Miner Res. 2014;29(11):2498–503.  
155. Saidenberg‐Kermanac’h N, Semerano L, Nunes H, Sadoun D, Guillot X, Boubaya M, et al. Bone 
fragility in sarcoidosis and relationships with calcium metabolism disorders: a cross sectional 
study on 142 patients. Arthritis Res Ther. 2014 Apr;16(2):R78.  
156. Boots AW, Drent M, Swennen ELR, Moonen HJJ, Bast A, Haenen GRMM. Antioxidant status 
associated with inflammation in sarcoidosis: A potential role for antioxidants. Respir Med. 
2009 Mar 1;103(3):364–72.  
157. Boots AW, Drent M, de Boer VCJ, Bast A, Haenen GRMM. Quercetin reduces markers of 
oxidative stress and inflammation in sarcoidosis. Clin Nutr. 2011 Aug 1;30(4):506–12.  
158. Pignone AM, Rosso AD, Fiori G, Matucci‐Cerinic M, Becucci A, Tempestini A, et al. Melatonin is 
a safe and effective treatment for chronic pulmonary and extrapulmonary sarcoidosis. J Pineal 
Res. 2006;41(2):95–100.  
159. Davis C, Bryan J, Hodgson J, Murphy K. Definition of the Mediterranean Diet: A Literature 
Review. Nutrients. 2015 Nov 5;7(11):9139–53.  

 

 

47 

 

160. Huether G, Poeggeler B, Reimer A, George A. Effect of tryptophan administration on 
circulating melatonin levels in chicks and rats: Evidence for stimulation of melatonin synthesis 
and release in the gastrointestinal tract. Life Sci. 1992 Jan 1;51(12):945–53.  
161. Abbasi B, Kimiagar M, Sadeghniiat K, Shirazi MM, Hedayati M, Rashidkhani B. The effect of 
magnesium supplementation on primary insomnia in elderly: A double‐blind placebo‐
controlled clinical trial. J Res Med Sci Off J Isfahan Univ Med Sci. 2012 Dec;17(12):1161–9.  
162. Wada K, Yata S, Akimitsu O, Krejci M, Noji T, Nakade M, et al. A tryptophan‐rich breakfast and 
exposure to light with low color temperature at night improve sleep and salivary melatonin 
level in Japanese students. J Circadian Rhythms. 2013 Dec;11(1):4.  
163. Lippi G, Franchini M. Vitamin K in neonates: facts and myths. Blood Transfus. 2011 Jan;9(1):4–
9.  
164. Heuer M, Clement K, Shan C, Thomas M. Resveratrol‐containing compositions for general 
health and vitality. 2008.  
165. Häkkinen SH, Kärenlampi SO, Heinonen IM, Mykkänen HM, Törrönen AR. Content of the 
Flavonols Quercetin, Myricetin, and Kaempferol in 25 Edible Berries. J Agric Food Chem. 1999 
Jun 1;47(6):2274–9.  
166. Ayerza R, Coates W, Lauria M. Chia seed (Salvia hispanica L.) as an omega‐3 fatty acid source 
for broilers: influence on fatty acid composition, cholesterol and fat content of white and dark 
meats, growth performance, and sensory characteristics. Poult Sci. 2002 Jun 1;81(6):826–37.  
167. Wardwell L, Chapman‐Novakofski K, Brewer MS. Effects of age, gender and chronic 
obstructive pulmonary disease on taste acuity. Int J Food Sci Nutr. 2009 Jan 1;60(sup6):84–97.  
168. Ito K, Kohzuki M, Takahashi T, Ebihara S. Improvement in taste sensitivity following pulmonary 
rehabilitation in patients with chronic obstructive pulmonary disease. J Rehabil Med. 
2014;46(9):932–6.  
169. Dewan NA, Bell CW, Moore J, Anderson B, Kirchain W, O’Donohue WJ. Smell and Taste 
Function in Subjects with Chronic Obstructive Pulmonary Disease: Effect of Long‐term Oxygen 
via Nasal Cannulas. CHEST. 1990 Mar 1;97(3):595–9.  
170. Williams LR, Cohen MH. Altered taste thresholds in lung cancer. Am J Clin Nutr. 1978 Jan 
1;31(1):122–5.  
171. Sweeney TD, Brain JD, Tryka AF, Godleski JJ. Retention of inhaled particles in hamsters with 
pulmonary fibrosis. Am Rev Respir Dis. 1983 Jul;128(1):138–43.  
172. Ikeda H, Itasaka M, Takahashi K, Komatani A. Prolonged lung retention of 123I‐IMP in 
pulmonary fibrosis. Ann Nucl Med. 1992 Aug;6(3):147–51.  
173. Verhagen JV. A role for lung retention in the sense of retronasal smell. Chemosens Percept. 
2015 Aug 1;8(2):78–84.  
174. Drent M. Vitamine K tekort: risicofactor bij longfibrose? 2017. (ildCARE Winter2017). 
175. Fortes C, Forastiere F, Farchi S, Mallone S, Trequattrinni T, et al. The protective effect of the 
Mediterranean diet on lung cancer. Nutr Cancer. 2003;46(1):30–7.  
176. Gutiérrez‐Carrasquilla L, Sánchez E, Hernández M, Polanco D, Salas‐Salvadó J, Betriu À, et al. 
Effects of Mediterranean Diet and Physical Activity on Pulmonary Function: A Cross‐Sectional 
Analysis in the ILERVAS Project. Nutrients [Internet]. 2019 Feb 3 [cited 2019 Apr 27];11(2). 
Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413220/ 
177. Sorli‐Aguilar M, Martin‐Lujan F, Flores‐Mateo G, Arija‐Val V, Basora‐Gallisa J, Sola‐Alberich R. 
Dietary patterns are associated with lung function among Spanish smokers without 
respiratory disease. BMC Pulm Med [Internet]. 2016 Nov 25 [cited 2019 Apr 27];16. Available 
from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123418/ 
178. Nutrition and Pulmonary Fibrosis | American Lung Association [Internet]. [cited 2019 Apr 25]. 
Available from: https://www.lung.org/lung‐health‐and‐diseases/lung‐disease‐
lookup/pulmonary‐fibrosis/patients/living‐well‐with‐pulmonary‐fibrosis/nutrition.html 
179. Booth SL. Vitamin K: food composition and dietary intakes. Food Nutr Res [Internet]. 2012 Apr 
2 [cited 2019 Apr 25];56. Available from: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321250/ 

 

 

48 

 

180. Gijsbers BL, Jie K‐SG, Vermeer C. Effect of food composition on vitamin K absorption in human 
volunteers. Br J Nutr. 1996;76(2):223–229.  
181. Erdman JW, International Life Sciences Institute, editors. Present knowledge in nutrition. 10. 
ed. Ames, Iowa: Wiley; 2012. 1305 p.  
182. Borel P, Preveraud D, Desmarchelier C. Bioavailability of vitamin E in humans: an update. Nutr 
Rev. 2013 Jun;71(6):319–31.  
183. Kaşıkcı MB, Bağdatlıoğlu N. Bioavailability of Quercetin. Curr Res Nutr Food Sci J. 2016 Oct 
25;4(Special Issue Nutrition in Conference October 2016):146–51.  
184. Walle T. Bioavailability of resveratrol. Ann N Y Acad Sci. 2011;1215(1):9–15. 
185. de Vries K, Strydom M, Steenkamp V. Bioavailability of resveratrol: Possibilities for 
enhancement. J Herb Med. 2018 Mar 1;11:71–7.  
186. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of Curcumin: Problems 
and Promises. Mol Pharm. 2007 Dec 1;4(6):807–18.  
187. Naumovski N, Blades BL, Roach PD. Food Inhibits the Oral Bioavailability of the Major Green 
Tea Antioxidant Epigallocatechin Gallate in Humans. Antioxidants. 2015 May 27;4(2):373–93.  
188. Kris‐Etherton PM, Hill AM. N‐3 fatty acids: food or supplements? J Am Diet Assoc. 2008 
Jul;108(7):1125–30.  
189. Tao L, Cao J, Wei W, Xie H, Zhang M, Zhang C. Protective role of rhapontin in experimental 
pulmonary fibrosis in vitro and in vivo. Int Immunopharmacol. 2017 Jun;47:38–46.  
190. Huang X, He Y, Chen Y, Wu P, Gui D, Cai H, et al. Baicalin attenuates bleomycin‐induced 
pulmonary fibrosis via adenosine A2a receptor related TGF‐β1‐induced ERK1/2 signaling 
pathway. BMC Pulm Med. 2016 Sep 23;16(1):132.  
191. Hu C, Wang Y, Fan Y, Li H, Wang C, Zhang J, et al. Lipidomics Revealed Idiopathic Pulmonary 
Fibrosis‐Induced Hepatic Lipid Disorders Corrected with Treatment of Baicalin in a Murine 
Model. AAPS J. 2015 May 1;17(3):711–22.  
192. Gao Y, Lu J, Zhang Y, Chen Y, Gu Z, Jiang X. Baicalein attenuates bleomycin‐induced pulmonary 
fibrosis in rats through inhibition of miR‐21. Pulm Pharmacol Ther. 2013 Dec;26(6):649–54.  
193. Ge A, Ma Y, Liu Y‐N, Li Y‐S, Gu H, Zhang J‐X, et al. Diosmetin prevents TGF‐β1‐induced 
epithelial‐mesenchymal transition via ROS/MAPK signaling pathways. Life Sci. 2016 May 
15;153:1–8.  
194. Soumyakrishnan S, Divya T, Kalayarasan S, Sriram N, Sudhandiran G. Daidzein exhibits anti‐
fibrotic effect by reducing the expressions of Proteinase activated receptor 2 and TGFβ1/smad 
mediated inflammation and apoptosis in Bleomycin‐induced experimental pulmonary fibrosis. 
Biochimie. 2014 Aug;103:23–36.  
195. Sriram N, Kalayarasan S, Manikandan R, Arumugam M, Sudhandiran G. Epigallocatechin 
gallate attenuates fibroblast proliferation and excessive collagen production by effectively 
intervening TGF‐β1 signalling. Clin Exp Pharmacol Physiol. 2015 Aug;42(8):849–59.  
196. Chen C‐Y, Peng W‐H, Wu L‐C, Wu C‐C, Hsu S‐L. Luteolin ameliorates experimental lung fibrosis 
both in vivo and in vitro: implications for therapy of lung fibrosis. J Agric Food Chem. 2010 Nov 
24;58(22):11653–61.  
197. Du G, Jin L, Han X, Song Z, Zhang H, Liang W. Naringenin: a potential immunomodulator for 
inhibiting lung fibrosis and metastasis. Cancer Res. 2009 Apr 1;69(7):3205–12.  
198. Zhang H, Liu X, Chen S, Wu J, Ye X, Xu L, et al. Tectorigenin inhibits the in vitro proliferation 
and enhances miR‐338* expression of pulmonary fibroblasts in rats with idiopathic pulmonary 
fibrosis. J Ethnopharmacol. 2010 Aug 19;131(1):165–73.  
199. Chen Y, Nie Y, Luo Y, Lin F, Zheng Y, Cheng G, et al. Protective effects of naringin against 
paraquat‐induced acute lung injury and pulmonary fibrosis in mice. Food Chem Toxicol Int J 
Publ Br Ind Biol Res Assoc. 2013 Aug;58:133–40.  
200. Turgut NH, Kara H, Elagoz S, Deveci K, Gungor H, Arslanbas E. The Protective Effect of Naringin 
against Bleomycin‐Induced Pulmonary Fibrosis in Wistar Rats. Pulm Med. 2016;2016:7601393.  
201. Dong Z‐W, Yuan Y‐F. Juglanin suppresses fibrosis and inflammation response caused by LPS in 
acute lung injury. Int J Mol Med. 2018 Jun;41(6):3353–65.  

 

 

49 

 

202. Zhang J, Chao L, Liu X, Shi Y, Zhang C, Kong L, et al. The potential application of strategic 
released apigenin from polymeric carrier in pulmonary fibrosis. Exp Lung Res. 2017 Nov 
26;43(9–10):359–69.  
203. Zheng Q, Tong M, Ou B, Liu C, Hu C, Yang Y. Isorhamnetin protects against bleomycin‐induced 
pulmonary fibrosis by inhibiting endoplasmic reticulum stress and epithelial‐mesenchymal 
transition. Int J Mol Med. 2019 Jan;43(1):117–26.  
204. Zhou C, Han W, Zhang P, Cai M, Wei D, Zhang C. Lycopene from tomatoes partially alleviates 
the bleomycin‐induced experimental pulmonary fibrosis in rats. Nutr Res N Y N. 2008 
Feb;28(2):122–30.  
205. Zhang J, Liu H, Song C, Zhang J, Wang Y, Lv C, et al. Astilbin ameliorates pulmonary fibrosis via 
blockade of Hedgehog signaling pathway. Pulm Pharmacol Ther. 2018;50:19–27.  
206. Jin M, Wang L, Wu Y, Zang B‐X, Tan L. Protective effect of hydroxysafflor yellow A on 
bleomycin‐ induced pulmonary inflammation and fibrosis in rats. Chin J Integr Med. 2018 
Jan;24(1):32–9.  
207. Jin M, Wu Y, Wang L, Zang B, Tan L. Hydroxysafflor Yellow A Attenuates Bleomycin‐induced 
Pulmonary Fibrosis in Mice. Phytother Res PTR. 2016 Apr;30(4):577–87.  
208. Pan R, Zhang Y, Zang B, Tan L, Jin M. Hydroxysafflor yellow A inhibits TGF‐β1‐induced 
activation of human fetal lung fibroblasts in vitro. J Pharm Pharmacol. 2016 Oct;68(10):1320–
30.  
209. Abidi A, Serairi Beji R, Kourda N, Ennigrou S, Ksouri R, Jameleddine S. Effect of Pistacia 
lentiscus oil on experimental pulmonary fibrosis. Tunis Med. 2016 Jul;94(7):401–6.  
210. Abidi A, Aissani N, Sebai H, Serairi R, Kourda N, Ben Khamsa S. Protective Effect of Pistacia 
lentiscus Oil Against Bleomycin‐Induced Lung Fibrosis and Oxidative Stress in Rat. Nutr Cancer. 
2017 Apr;69(3):490–7.  
211. Kennedy JI, Chandler DB, Fulmer JD, Wert MB, Grizzle WE. Dietary fish oil inhibits bleomycin‐
induced pulmonary fibrosis in the rat. Exp Lung Res. 1989 Mar;15(2):315–29.  
212. Baybutt RC, Rosales C, Brady H, Molteni A. Dietary fish oil protects against lung and liver 
inflammation and fibrosis in monocrotaline treated rats. Toxicology. 2002 Jun 14;175(1–3):1–
13.  
213. Silva LP, Lemos APC, Curi R, Azevedo RB. Effects of fish oil treatment on bleomycin‐induced 
pulmonary fibrosis in mice. Cell Biochem Funct. 2006 Oct;24(5):387–96.  
214. Liu L, Qian H, Yin H, He J, Zhang P, Wang Z. [Unsaturated fatty acid of Actinidia chinesis Planch 
seed oil enhances the antioxidative stress ability of rats with pulmonary fibrosis through 
activating Keap 1/Nrf 2 signaling pathway]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi Chin J Cell Mol 
Immunol. 2016 Apr;32(4):479–83.  
215. Tahir I, Khan MR, Shah NA, Aftab M. Evaluation of phytochemicals, antioxidant activity and 
amelioration of pulmonary fibrosis with Phyllanthus emblica leaves. BMC Complement Altern 
Med [Internet]. 2016 Oct 24 [cited 2019 Feb 9];16. Available from: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5078946/ 
216. Tao L, Yang J, Cao F, Xie H, Zhang M, Gong Y, et al. Mogroside IIIE, a Novel Anti‐Fibrotic 
Compound, Reduces Pulmonary Fibrosis through Toll‐Like Receptor 4 Pathways. J Pharmacol 
Exp Ther. 2017;361(2):268–79.  
217. Bahri S, Abdennabi R, Mlika M, Neji G, Jameleddine S, Ali RB. Effect of Phoenix dactylifera L. 
Sap Against Pulmonary Fibrosis and Oxidative Stress in Rats: Phytochemical and Therapeutic 
Assessment. Nutr Cancer. 2019 Jan 9;1–11.  
218. Javad‐Mousavi SA, Hemmati AA, Mehrzadi S, Hosseinzadeh A, Houshmand G, Rashidi 
Nooshabadi MR, et al. Protective effect of Berberis vulgaris fruit extract against Paraquat‐
induced pulmonary fibrosis in rats. Biomed Pharmacother. 2016 Jul 1;81:329–36.  
219. Chilakapati SR, Serasanambati M, Manikonda PK, Chilakapati DR, Watson RR. Passion fruit 
peel extract attenuates bleomycin‐induced pulmonary fibrosis in mice. Can J Physiol 
Pharmacol. 2014 Aug;92(8):631–9.  

 

 

50 

 

220. Chakraborty K, Dey A, Bhattacharyya A, Dasgupta SC. Anti‐fibrotic effect of black tea (Camellia 
sinensis) extract in experimental pulmonary fibrosis. Tissue Cell. 2019 Feb;56:14–22.  
221. You H, Wei L, Sun W‐L, Wang L, Yang Z‐L, Liu Y, et al. The green tea extract epigallocatechin‐3‐
gallate inhibits irradiation‐induced pulmonary fibrosis in adult rats. Int J Mol Med. 2014 
Jul;34(1):92–102.  
222. Sriram N, Kalayarasan S, Sudhandiran G. Enhancement of antioxidant defense system by 
epigallocatechin‐3‐gallate during bleomycin induced experimental pulmonary fibrosis. Biol 
Pharm Bull. 2008 Jul;31(7):1306–11.  
223. Kim H‐R, Park B‐K, Oh Y‐M, Lee Y‐S, Lee D‐S, Kim H‐K, et al. Green tea extract inhibits 
paraquat‐induced pulmonary fibrosis by suppression of oxidative stress and endothelin‐l 
expression. Lung. 2006 Oct;184(5):287–95.  
224. Donà M, Dell’Aica I, Calabrese F, Benelli R, Morini M, Albini A, et al. Neutrophil restraint by 
green tea: inhibition of inflammation, associated angiogenesis, and pulmonary fibrosis. J 
Immunol Baltim Md 1950. 2003 Apr 15;170(8):4335–41.  
225. INRA. Phenol‐explorer [Internet]. 2015 [cited 2019 Jul 5]. Available from: http://phenol
explorer.eu/contents/polyphenol/592 
226. USDA. Food Composition Databases Show Nutrients List [Internet]. 2019 [cited 2019 Jul 5]. 
Available from: https://ndb.nal.usda.gov/ndb/nutrients 

Universiteit of Hogeschool
Viktor Lowie Proesmans
Maastricht University
Publicatiejaar
2019
Promotor(en)
prof. dr. Aalt Bast
Kernwoorden
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