Idiopathic pulmonary fibrosis pathophysiology: Difference between revisions

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==Genetics==
==Microscopic pathology==
==Microscopic pathology==
* The microscopic feature associated with idiopathic pulmonary fibrosis is named as "Usual Interstitial Pneumonia (UIP)".<ref name="pmid11519507">{{cite journal| author=Gross TJ, Hunninghake GW| title=Idiopathic pulmonary fibrosis. | journal=N Engl J Med | year= 2001 | volume= 345 | issue= 7 | pages= 517-25 | pmid=11519507 | doi=10.1056/NEJMra003200 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11519507  }}</ref>
* The microscopic feature associated with idiopathic pulmonary fibrosis is named as "Usual Interstitial Pneumonia (UIP)".<ref name="pmid11519507">{{cite journal| author=Gross TJ, Hunninghake GW| title=Idiopathic pulmonary fibrosis. | journal=N Engl J Med | year= 2001 | volume= 345 | issue= 7 | pages= 517-25 | pmid=11519507 | doi=10.1056/NEJMra003200 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11519507  }}</ref>

Revision as of 00:11, 15 March 2018

Idiopathic pulmonary fibrosis Microchapters

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Overview

Pathophysiology

Normal lung tissue

  • Lungs are composed normally of extracellular collagen which allows the lungs to exert their breathing efforts.
  • Different collagen types in the lung include the following:[1]
    • Type 1 and type 3 compose most of the lung tissue
    • Type 2 is the main component of the cartilage of the main bronchi
    • Type 4 forms the basement membrane
    • Type 5 forms the interstitial tissue
  • Normally, collagen is degraded and produced regularly to preserve the normal lung tissue.[2]
  • Collagen is produced by fibroblasts which also can degrade some of the collagen produced.
  • Metalloproteinases produced by fibroblasts, neutrophils, and macrophages have the main role in degrading collagen.

Pathogenesis

  • Interstitial lung disease is a group of disorders that involve pulmonary parenchyma.
  • The exact pathogenesis of these disorders is not fully understood.
  • There are multiple initiating factors that cause pulmonary injury. However, immunopathogenic responses of lung tissue are quite similar.
  • There are two major histopathologic patterns in response to lung injury which include:


Algorithm showing pathophysiology of Interstitial Lung Disease[3]


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tissue injury in lungs
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parenchymal injury
 
 
 
 
 
 
 
 
 
Vascular injury
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mast cells in lungs in response to tissue injury
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LPA6, LPA2, and LPA4 receptors[4]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Decreased sFRP-1 (secreted frizzled-related protein 1) in fibroblasts[5]
 
Secretes tryptase
 
Transforming growth factor-β (TGF-β)[6]
 
 
 
 
Insulin-like growth factor (IGF) signalling[5]
 
 
 
 
 
 
 
Reduced expression of angiogenic factors,
vascular endothelial growth factor (VEGF)[7]
 
Elevation of angiostatic factors,
pigment epithelium-derived factor[8]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wnt/β-catenin signalling pathway[9][10]
 
PAR-2/protein kinase (PK)C-α/Raf-1/p44/42 signaling pathway[11]
 
Upregulation of Egr-1 (early growth response protein 1)[12]
 
IGF-binding protein 5 (IGFBP-5)[13]
 
 
 
IGF-binding protein 3 (IGFBP-3)
 
 
 
 
 
 
 
Loss of endothelial barrier function
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dysregulation of repair in lung tissue and activation of fibroblasts[14]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Regulates transforming growth factor-β (TGF-β)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Induction of syndecan-2 (SDC2)[15]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Activation,proliferation, and migration of fibroblast to the site of injury
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fibroblasts
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Altered PTEN (phosphatase and tensin homologue)/Akt axis
 
 
 
 
Acquire contractile stress fibres
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inactivates Fox (forkhead box) O3a[16]
 
 
 
 
Protomyofibroblast, composed of cytoplasmic actins
 
Pleural mesothelial cells (PMCs)[17][18]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Downregulation of caveolin-1 (cav-1) and Fas expression[19]
 
 
 
 
De novo expression of α-smooth muscle actin (α-SMA)
 
TGF-β1-dependent mesothelial–mesenchymal transition
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fibroblast resistant to apoptosis[20]
 
 
 
 
 
 
Myofibroblasts[21]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Different ranges of contractions mediated by RhoA/Rho-associated kinase
 
 
Changes in intracellular calcium concentrations
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recruitement of fibrocytes in lungs
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lock step mechanism of cyclic and contractile events[22]
 
 
 
 
 
 
 
 
 
T-helper cell type 2 on site of injury[23][24]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Upregulation of C-X-C chemokine receptor type 4 (CXCR4)
on fibrocytes and its ligand
CXCL12 (stromal cell-derived factor 1)[25]
 
 
 
 
 
Excess extracellular matrix production
 
 
 
 
 
Exerting traction force
 
 
 
 
 
 
 
 
 
Interleukin-13
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Migration of fibrocytes to the site of injury[26]
 
 
 
 
 
Tissue remodelling[27]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alternate pathway activation of macrophages[28]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lung Fibrosis
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Microscopic pathology

  • The microscopic feature associated with idiopathic pulmonary fibrosis is named as "Usual Interstitial Pneumonia (UIP)".[29]
  • The histologic findings in UIP include the following:
    • Proliferation of mesenchymal cells
    • Areas of different fibrosis degree
    • Dense deposition of collagen fibers
    • Overproduction of extracellular matrix
    • Poor differentiated pulmonary architecture
    • Honeycomb cysts (subpleural cysts)

Gross pathology

  • The most important characteristics of idiopathic pulmonary fibrosis on gross pathology are:[30]
    • Inferior lobes fibrosis
    • Cobblestone appearance of the pleura
    • Honeycomb appearance of the lung
    • Airspaces enlargement
    • Fibrotic retraction of the airways
Honeycomb appearance of a fibrotic lung.
Case courtesy of A.Prof Frank Gaillard, <a href="https://radiopaedia.org/">Radiopaedia.org</a>. From the case <a href="https://radiopaedia.org/cases/8621">rID: 8621</a> via www.radiopaedia.org

References

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  27. Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G (2007). "The myofibroblast: one function, multiple origins". Am J Pathol. 170 (6): 1807–16. doi:10.2353/ajpath.2007.070112. PMC 1899462. PMID 17525249.
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  30. Wolters PJ, Collard HR, Jones KD (2014). "Pathogenesis of idiopathic pulmonary fibrosis". Annu Rev Pathol. 9: 157–79. doi:10.1146/annurev-pathol-012513-104706. PMC 4116429. PMID 24050627.

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