Interstitial lung disease: Difference between revisions

	Interstitial Lung Disease
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Overview
Classification Fibrosis lung response Occupational lung disease Drug-induced lung injury Radiation-induced lung injury Smoking related interstitial lung disease Idiopathic interstitial pneumonia Pulmonary alveolar proteinosis Lymphocytic infiltrative disorders Pulmonary lymphangioleiomyomatosis Pulmonary hemorrhage syndromes Interstitial lung disease associated with systemic diseases Granulomatous lung response
Pathophysiology
Differentiating Interstitial Lung Disease from other Diseases
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Revision as of 22:38, 7 March 2018

For the WikiPatient page for this topic, click here

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Saarah T. Alkhairy, M.D.

Synonyms and keywords: Diffuse parenchymal lung disease; DPLD; ILD

Overview

Classification

Interstitial lung disease may be classified on the basis of lung response to tissue injury and include:^[1]

Lung response: Granulomatous
Lung response: Alveolitis, interstitial inflammation, and fibrosis

Interstitial lung disease

Lung Response:
Granulomatous

Lung Response:
Alveolitis,
Interstitial Inflammation,
and Fibrosis

Known

Idiopathic (Unknown)

Hypersensitivity pneumonitis (organic dusts)

Inorganic dusts

Sarcoidosis

Lymphomatoid granulomatosis

Granulomatous vasculitides

Bronchocentric granulomatosis

Beryllium

Silica

Eosinophilic granulomatosis with polyangiitis (Churg Strauss syndrome)

Granulomatosis with polyangiitis (Wegener)

Known cause

Idiopathic (Unknown)

Drug-induced pulmonary toxicity

Occupational and environmental exposure

Radiation-induced lung injury

Aspiration pneumonia

Smoking-related

Residual of acute respiratory distress syndrome

Inhaled inorganic dust

Inhaled organic dusts

Inhaled agents other than inorganic or organic dusts

Desquamative interstitial pneumonia

Respiratory bronchiolitis–associated interstitial lung disease

Pulmonary Langerhans cell granulomatosis

Pulmonary alveolar proteinosis

Idiopathic interstitial pneumonias

Lymphocytic infiltrative disorders
(lymphocytic interstitial pneumonitis
associated with connective tissue disease)

Connective tissue
diseases

Gastrointestinal or
liver diseases

Inherited diseases

Graft-versus-host disease

Pulmonary hemorrhage syndromes

Eosinophilic
pneumonias

Lymphangioleiomyomatosis

Amyloidosis

Major idiopathic interstitial pneumonias

Rare idiopathic interstitial pneumonias

Unclassifiable idiopathic interstitial pneumonias

• Idiopathic pulmonary fibrosis
• Idiopathic nonspecific interstitial pneumonia
• Respiratory bronchiolitis-interstitial lung disease
• Desquamative interstitial pneumonia
• Cryptogenic organising pneumonia
• Acute interstitial pneumonia

• Idiopathic lymphoid interstitial pneumonia
• Idiopathic pleuroparenchymal fibroelastosis

• Systemic lupus erythematosus
• Rheumatoid arthritis
• Ankylosing spondylitis
• Systemic sclerosis
• Sjögren syndrome
• Polymyositis
• Dermatomyositis

• Crohn disease
• Primary biliary cirrhosis
• Chronic active hepatitis
• Ulcerative colitis

• Tuberous sclerosis
• Neurofibromatosis
• Niemann-Pick disease
• Gaucher disease
• Hermansky-Pudlak syndrome

• Bone marrow transplantation
• Solid organ transplantation

• Goodpasture syndrome
• Idiopathic pulmonary hemosiderosis
• Isolated pulmonary capillaritis

Pathophysiology

Algorithm showing pathophysiology of Interstitial Lung Disease^[2]

Tissue injury in lungs

Parenchymal injury

Vascular injury

Mast cells in lungs in response to tissue injury

LPA6, LPA2, and LPA4 receptors

Decreased sFRP-1 (secreted frizzled-related protein 1) in fibroblasts

Secretes tryptase

Transforming growth factor-β (TGF-β)

Insulin-like growth factor (IGF) signalling^[3]

Reduced expression of angiogenic factors,
vascular endothelial growth factor (VEGF)

Elevation of angiostatic factors,
pigment epithelium-derived factor

Wnt/β-catenin signalling pathway

PAR-2/protein kinase (PK)C-α/Raf-1/p44/42 signaling pathway

Upregulation of Egr-1 (early growth response protein 1)^[4]

IGF-binding protein 5 (IGFBP-5)^[5]

IGF-binding protein 3 (IGFBP-3)

Loss of endothelial barrier function

Dysregulation of repair in lung tissue and activation of fibroblasts

Regulates transforming growth factor-β (TGF-β)

Induction of syndecan-2 (SDC2)^[6]

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^[7]

Protomyofibroblast, composed of cytoplasmic actins

Pleural mesothelial cells (PMCs)

Downregulation of caveolin-1 (cav-1) and Fas expression^[8]

De novo expression of α-smooth muscle actin (α-SMA)

TGF-β1-dependent mesothelial–mesenchymal transition

Fibroblast resistant to apoptosis^[9]

Myofibroblasts^[10]

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^[11]

T-helper cell type 2 on site of injury

Upregulation of C-X-C chemokine receptor type 4 (CXCR4)
on fibrocytes and its ligand
CXCL12 (stromal cell-derived factor 1)

Excess extracellular matrix production

Exerting traction force

Interleukin-13

Migration of fibrocytes to the site of injury

Tissue remodelling^[12]

Alternate pathway activation of macrophages

Lung Fibrosis

References

Template:Respiratory pathology

de:Interstitielle Lungenerkrankung fi:Keuhkoparenkyymisairaudet

Template:WikiDoc Sources

↑ Kasper, Dennis (2015). "315: Interstitial Lung Diseases". In Talmadge, E. King, Jr. Harrison's principles of internal medicine. New York: McGraw Hill Education. ISBN 0071802150.
↑ Bagnato G, Harari S (2015). "Cellular interactions in the pathogenesis of interstitial lung diseases". Eur Respir Rev. 24 (135): 102–14. doi:10.1183/09059180.00003214. PMID 25726561.
↑ Hsu E, Shi H, Jordan RM, Lyons-Weiler J, Pilewski JM, Feghali-Bostwick CA (2011). "Lung tissues in patients with systemic sclerosis have gene expression patterns unique to pulmonary fibrosis and pulmonary hypertension". Arthritis Rheum. 63 (3): 783–94. doi:10.1002/art.30159. PMC 3139818. PMID 21360508.
↑ Yasuoka H, Hsu E, Ruiz XD, Steinman RA, Choi AM, Feghali-Bostwick CA (2009). "The fibrotic phenotype induced by IGFBP-5 is regulated by MAPK activation and egr-1-dependent and -independent mechanisms". Am J Pathol. 175 (2): 605–15. doi:10.2353/ajpath.2009.080991. PMC 2716960. PMID 19628764.
↑ Bhattacharyya S, Wu M, Fang F, Tourtellotte W, Feghali-Bostwick C, Varga J (2011). "Early growth response transcription factors: key mediators of fibrosis and novel targets for anti-fibrotic therapy". Matrix Biol. 30 (4): 235–42. doi:10.1016/j.matbio.2011.03.005. PMC 3135176. PMID 21511034.
↑ Ruiz XD, Mlakar LR, Yamaguchi Y, Su Y, Larregina AT, Pilewski JM; et al. (2012). "Syndecan-2 is a novel target of insulin-like growth factor binding protein-3 and is over-expressed in fibrosis". PLoS One. 7 (8): e43049. doi:10.1371/journal.pone.0043049. PMC 3416749. PMID 22900087.
↑ Nho RS, Peterson M, Hergert P, Henke CA (2013). "FoxO3a (Forkhead Box O3a) deficiency protects Idiopathic Pulmonary Fibrosis (IPF) fibroblasts from type I polymerized collagen matrix-induced apoptosis via caveolin-1 (cav-1) and Fas". PLoS One. 8 (4): e61017. doi:10.1371/journal.pone.0061017. PMC 3620276. PMID 23580232.
↑ Del Galdo F, Sotgia F, de Almeida CJ, Jasmin JF, Musick M, Lisanti MP; et al. (2008). "Decreased expression of caveolin 1 in patients with systemic sclerosis: crucial role in the pathogenesis of tissue fibrosis". Arthritis Rheum. 58 (9): 2854–65. doi:10.1002/art.23791. PMC 2770094. PMID 18759267.
↑ Thannickal VJ, Horowitz JC (2006). "Evolving concepts of apoptosis in idiopathic pulmonary fibrosis". Proc Am Thorac Soc. 3 (4): 350–6. doi:10.1513/pats.200601-001TK. PMC 2231523. PMID 16738200.
↑ Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA (2002). "Myofibroblasts and mechano-regulation of connective tissue remodelling". Nat Rev Mol Cell Biol. 3 (5): 349–63. doi:10.1038/nrm809. PMID 11988769.
↑ Castella LF, Buscemi L, Godbout C, Meister JJ, Hinz B (2010). "A new lock-step mechanism of matrix remodelling based on subcellular contractile events". J Cell Sci. 123 (Pt 10): 1751–60. doi:10.1242/jcs.066795. PMID 20427321.
↑ 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.

[1] Kasper, Dennis (2015). "315: Interstitial Lung Diseases". In Talmadge, E. King, Jr. Harrison's principles of internal medicine. New York: McGraw Hill Education. ISBN 0071802150.

[pmid25726561-2] Bagnato G, Harari S (2015). "Cellular interactions in the pathogenesis of interstitial lung diseases". Eur Respir Rev. 24 (135): 102–14. doi:10.1183/09059180.00003214. PMID 25726561.

[pmid21360508-3] Hsu E, Shi H, Jordan RM, Lyons-Weiler J, Pilewski JM, Feghali-Bostwick CA (2011). "Lung tissues in patients with systemic sclerosis have gene expression patterns unique to pulmonary fibrosis and pulmonary hypertension". Arthritis Rheum. 63 (3): 783–94. doi:10.1002/art.30159. PMC 3139818. PMID 21360508.

[pmid19628764-4] Yasuoka H, Hsu E, Ruiz XD, Steinman RA, Choi AM, Feghali-Bostwick CA (2009). "The fibrotic phenotype induced by IGFBP-5 is regulated by MAPK activation and egr-1-dependent and -independent mechanisms". Am J Pathol. 175 (2): 605–15. doi:10.2353/ajpath.2009.080991. PMC 2716960. PMID 19628764.

[pmid21511034-5] Bhattacharyya S, Wu M, Fang F, Tourtellotte W, Feghali-Bostwick C, Varga J (2011). "Early growth response transcription factors: key mediators of fibrosis and novel targets for anti-fibrotic therapy". Matrix Biol. 30 (4): 235–42. doi:10.1016/j.matbio.2011.03.005. PMC 3135176. PMID 21511034.

[pmid22900087-6] Ruiz XD, Mlakar LR, Yamaguchi Y, Su Y, Larregina AT, Pilewski JM; et al. (2012). "Syndecan-2 is a novel target of insulin-like growth factor binding protein-3 and is over-expressed in fibrosis". PLoS One. 7 (8): e43049. doi:10.1371/journal.pone.0043049. PMC 3416749. PMID 22900087.

[pmid23580232-7] Nho RS, Peterson M, Hergert P, Henke CA (2013). "FoxO3a (Forkhead Box O3a) deficiency protects Idiopathic Pulmonary Fibrosis (IPF) fibroblasts from type I polymerized collagen matrix-induced apoptosis via caveolin-1 (cav-1) and Fas". PLoS One. 8 (4): e61017. doi:10.1371/journal.pone.0061017. PMC 3620276. PMID 23580232.

[pmid18759267-8] Del Galdo F, Sotgia F, de Almeida CJ, Jasmin JF, Musick M, Lisanti MP; et al. (2008). "Decreased expression of caveolin 1 in patients with systemic sclerosis: crucial role in the pathogenesis of tissue fibrosis". Arthritis Rheum. 58 (9): 2854–65. doi:10.1002/art.23791. PMC 2770094. PMID 18759267.

[pmid16738200-9] Thannickal VJ, Horowitz JC (2006). "Evolving concepts of apoptosis in idiopathic pulmonary fibrosis". Proc Am Thorac Soc. 3 (4): 350–6. doi:10.1513/pats.200601-001TK. PMC 2231523. PMID 16738200.

[pmid11988769-10] Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA (2002). "Myofibroblasts and mechano-regulation of connective tissue remodelling". Nat Rev Mol Cell Biol. 3 (5): 349–63. doi:10.1038/nrm809. PMID 11988769.

[pmid20427321-11] Castella LF, Buscemi L, Godbout C, Meister JJ, Hinz B (2010). "A new lock-step mechanism of matrix remodelling based on subcellular contractile events". J Cell Sci. 123 (Pt 10): 1751–60. doi:10.1242/jcs.066795. PMID 20427321.

[pmid17525249-12] 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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[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

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[11]

[12]

@@ Line 54: / Line 54: @@
 ==Pathophysiology==
-<div style="text-align: center;">'''Algorithm showing pathophysiology of Interstitial Lung Disease'''</div>
+<div style="text-align: center;">'''Algorithm showing pathophysiology of Interstitial Lung Disease'''<ref name="pmid25726561">{{cite journal| author=Bagnato G, Harari S| title=Cellular interactions in the pathogenesis of interstitial lung diseases. | journal=Eur Respir Rev | year= 2015 | volume= 24 | issue= 135 | pages= 102-14 | pmid=25726561 | doi=10.1183/09059180.00003214 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25726561  }} </ref></div>
@@ Line 64: / Line 64: @@
 {{Family tree| | | | | | | | R01 | | | | | | | |!| | | | | | | | | | | R02 | | | | | | | R01=[[Mast cell]]s in [[lungs]] in response to tissue injury|R02= LPA6, LPA2, and LPA4 receptors }}
 {{Family tree| | | | | | |,|-|^|-|.| | | | | | |!| | | | | | | | | |,|-|^|-|.| | | | | | }}
-{{Family tree| | Q01 | | Q06 | | Q03 | | | | | Q02 | | | | | | | | Q04 | | Q05 | | | | | Q01=Decreased [[Secreted frizzled-related protein 1|sFRP-1 (secreted frizzled-related protein 1)]] in [[fibroblasts]]|Q02= [[Insulin-like growth factor]] ([[IGF]]) signalling|Q03=[[Transforming growth factor-β]] ([[TGF-β]])|Q04= Reduced expression of angiogenic factors,<br>[[vascular endothelial growth factor]] (VEGF)|Q05=Elevation of angiostatic factors,<br>pigment epithelium-derived factor|Q06=Secretes [[tryptase]]}}
+{{Family tree| | Q01 | | Q06 | | Q03 | | | | | Q02 | | | | | | | | Q04 | | Q05 | | | | | Q01=Decreased [[Secreted frizzled-related protein 1|sFRP-1 (secreted frizzled-related protein 1)]] in [[fibroblasts]]|Q02= [[Insulin-like growth factor]] ([[IGF]]) signalling<ref name="pmid21360508">{{cite journal| author=Hsu E, Shi H, Jordan RM, Lyons-Weiler J, Pilewski JM, Feghali-Bostwick CA| title=Lung tissues in patients with systemic sclerosis have gene expression patterns unique to pulmonary fibrosis and pulmonary hypertension. | journal=Arthritis Rheum | year= 2011 | volume= 63 | issue= 3 | pages= 783-94 | pmid=21360508 | doi=10.1002/art.30159 | pmc=3139818 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21360508  }} </ref>|Q03=[[Transforming growth factor-β]] ([[TGF-β]])|Q04= Reduced expression of angiogenic factors,<br>[[vascular endothelial growth factor]] (VEGF)|Q05=Elevation of angiostatic factors,<br>pigment epithelium-derived factor|Q06=Secretes [[tryptase]]}}
 {{Family tree| | |!| | | |!| | | |!| | | |,|-|-|^|-|-|.| | | | | | |`|-|v|-|'| | | | | | }}
-{{Family tree| | P01 | | P02 | | P05 | | P04 | | | | P03 |.| | | | | | P06 | | | | | P01=[[Wnt signaling pathway|Wnt/β-catenin signalling pathway]]|P02=PAR-2/protein kinase (PK)C-α/Raf-1/p44/42 signaling pathway|P03=[[IGFBP3|IGF-binding protein 3 (IGFBP-3]])|P04=[[Insulin-like growth factor binding protein|IGF-binding protein 5 (IGFBP-5)]]|P05=Upregulation of Egr-1 (early growth response protein 1)|P06=Loss of [[endothelial]] barrier function }}
+{{Family tree| | P01 | | P02 | | P05 | | P04 | | | | P03 |.| | | | | | P06 | | | | | P01=[[Wnt signaling pathway|Wnt/β-catenin signalling pathway]]|P02=PAR-2/protein kinase (PK)C-α/Raf-1/p44/42 signaling pathway|P03=[[IGFBP3|IGF-binding protein 3 (IGFBP-3]])|P04=[[Insulin-like growth factor binding protein|IGF-binding protein 5 (IGFBP-5)]]<ref name="pmid21511034">{{cite journal| author=Bhattacharyya S, Wu M, Fang F, Tourtellotte W, Feghali-Bostwick C, Varga J| title=Early growth response transcription factors: key mediators of fibrosis and novel targets for anti-fibrotic therapy. | journal=Matrix Biol | year= 2011 | volume= 30 | issue= 4 | pages= 235-42 | pmid=21511034 | doi=10.1016/j.matbio.2011.03.005 | pmc=3135176 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21511034  }} </ref>|P05=Upregulation of Egr-1 (early growth response protein 1)<ref name="pmid19628764">{{cite journal| author=Yasuoka H, Hsu E, Ruiz XD, Steinman RA, Choi AM, Feghali-Bostwick CA| title=The fibrotic phenotype induced by IGFBP-5 is regulated by MAPK activation and egr-1-dependent and -independent mechanisms. | journal=Am J Pathol | year= 2009 | volume= 175 | issue= 2 | pages= 605-15 | pmid=19628764 | doi=10.2353/ajpath.2009.080991 | pmc=2716960 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19628764  }} </ref>|P06=Loss of [[endothelial]] barrier function }}
 {{Family tree| |!| |!| | |!| | | |!| | | |!| | | | | |!| |!| | | | | | |!| | | | | | | | }}
 {{Family tree| O01 |!| | |!| | | |`|-|-|-|^|.| | | | |!| O02 | | | | | |!| | | | | | | | O01=Dysregulation of repair in [[lung tissue]]  and activation of [[fibroblasts]]|O02=Regulates [[transforming growth factor-β]] ([[TGF-β]]) }}
 {{Family tree| | | |!| | |!| | | | | | | | |!| | | | |!|,|'| | | | | | |!| | | | | | | | }}
-{{Family tree| | | |!| | |!| | | | | | | | |!| | | | A02 | | | | | | | |!| | | | | | | | A01=|A02=Induction of [[syndecan-2|syndecan-2 (SDC2)]]}}
+{{Family tree| | | |!| | |!| | | | | | | | |!| | | | A02 | | | | | | | |!| | | | | | | | A01=|A02=Induction of [[syndecan-2|syndecan-2 (SDC2)]]<ref name="pmid22900087">{{cite journal| author=Ruiz XD, Mlakar LR, Yamaguchi Y, Su Y, Larregina AT, Pilewski JM et al.| title=Syndecan-2 is a novel target of insulin-like growth factor binding protein-3 and is over-expressed in fibrosis. | journal=PLoS One | year= 2012 | volume= 7 | issue= 8 | pages= e43049 | pmid=22900087 | doi=10.1371/journal.pone.0043049 | pmc=3416749 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22900087  }} </ref>}}
 {{Family tree| | | |!| | |!| | | | | | | | |!| | | | |!| | | | | | | | |!| | | | | | | | }}
 {{Family tree| | | |!| | |`|-|-|-|-|-|-|-|.|!|,|-|-|-|'| | | | | | | | |!| | | | | | | | }}
@@ Line 79: / Line 79: @@
 {{Family tree| | | | | | | | | | | | D01 | |!| | D02 | | | | | | | | | |!| | | | | | | | D01=Altered PTEN (phosphatase and tensin homologue)/Akt axis|D02=Acquire contractile stress fibres}}
 {{Family tree| | | | | | | | | | | | |!| | |!| | |!| | | | | | | | | | |!| | | | | | | | }}
-{{Family tree| | | | | | | | | | | | G01 | |!| | G02 | | G03 | | | | | |!| | | | | | | | G01= Inactivates [[FOX proteins|Fox (forkhead box) O3a]]|G02=Protomyofibroblast, composed of cytoplasmic [[actins]]|G03=[[Pleural]] [[mesothelial]] cells (PMCs)}}
+{{Family tree| | | | | | | | | | | | G01 | |!| | G02 | | G03 | | | | | |!| | | | | | | | G01= Inactivates [[FOX proteins|Fox (forkhead box) O3a]]<ref name="pmid23580232">{{cite journal| author=Nho RS, Peterson M, Hergert P, Henke CA| title=FoxO3a (Forkhead Box O3a) deficiency protects Idiopathic Pulmonary Fibrosis (IPF) fibroblasts from type I polymerized collagen matrix-induced apoptosis via caveolin-1 (cav-1) and Fas. | journal=PLoS One | year= 2013 | volume= 8 | issue= 4 | pages= e61017 | pmid=23580232 | doi=10.1371/journal.pone.0061017 | pmc=3620276 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23580232  }} </ref>|G02=Protomyofibroblast, composed of cytoplasmic [[actins]]|G03=[[Pleural]] [[mesothelial]] cells (PMCs)}}
 {{Family tree| | | | | | | | | | | | |!| | |!| | |!| | | |!| | | | | | |!| | | | | | | | }}
-{{Family tree| | | | | | | | | | | | H01 | |!| | H02 | | H03 | | | | | |!| | | | | | | | H01= Downregulation of [[Caveolin 1|caveolin-1 (cav-1)]] and Fas expression|H02=De novo expression of α-smooth muscle actin (α-SMA)|H03=TGF-β1-dependent mesothelial–mesenchymal transition}}
+{{Family tree| | | | | | | | | | | | H01 | |!| | H02 | | H03 | | | | | |!| | | | | | | | H01= Downregulation of [[Caveolin 1|caveolin-1 (cav-1)]] and Fas expression<ref name="pmid18759267">{{cite journal| author=Del Galdo F, Sotgia F, de Almeida CJ, Jasmin JF, Musick M, Lisanti MP et al.| title=Decreased expression of caveolin 1 in patients with systemic sclerosis: crucial role in the pathogenesis of tissue fibrosis. | journal=Arthritis Rheum | year= 2008 | volume= 58 | issue= 9 | pages= 2854-65 | pmid=18759267 | doi=10.1002/art.23791 | pmc=2770094 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18759267  }} </ref>|H02=De novo expression of α-smooth muscle actin (α-SMA)|H03=TGF-β1-dependent mesothelial–mesenchymal transition}}
 {{Family tree| | | | | | | | | | | | |!| | |!| | | |!| |!| | | | | | | |!| | | | | | | | }}
-{{Family tree| | | | | | | | | | | | I01 | |!| | | | I02 | | | | | | | |!| | | | | | | | I01=[[Fibroblast]] resistant to [[apoptosis]]|I02=[[Myofibroblasts]]}}
+{{Family tree| | | | | | | | | | | | I01 | |!| | | | I02 | | | | | | | |!| | | | | | | | I01=[[Fibroblast]] resistant to [[apoptosis]]<ref name="pmid16738200">{{cite journal| author=Thannickal VJ, Horowitz JC| title=Evolving concepts of apoptosis in idiopathic pulmonary fibrosis. | journal=Proc Am Thorac Soc | year= 2006 | volume= 3 | issue= 4 | pages= 350-6 | pmid=16738200 | doi=10.1513/pats.200601-001TK | pmc=2231523 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16738200  }} </ref>|I02=[[Myofibroblasts]]<ref name="pmid11988769">{{cite journal| author=Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA| title=Myofibroblasts and mechano-regulation of connective tissue remodelling. | journal=Nat Rev Mol Cell Biol | year= 2002 | volume= 3 | issue= 5 | pages= 349-63 | pmid=11988769 | doi=10.1038/nrm809 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11988769  }} </ref>}}
 {{Family tree| | | | | | | | | | | | | | | |!| | | |!| |!| | | | | | | |!| | | | | | | | }}
 {{Family tree| | | | | | | | | | | | | | | |!| | | |!| |)|-|-|-|-|.| | |!| | | | | | | | }}
 {{Family tree| | | | | | | | | | | | | | | |!| | | |!| J02 | | | J03 | |!| | | | | | | | J02=Different ranges of contractions mediated by RhoA/Rho-associated kinase|J03=Changes in intracellular calcium concentrations}}
 {{Family tree| | | | | | | | | | | | | | | |!| | | |!| | |`|-|v|-|'| | |!| | | | | | | | }}
-{{Family tree| | | | | | | | K01 | | | | | |!| |,|-|'| | | | K02 | | | |!| | | | | K03 | K01=Recruitement of fibrocytes in [[lungs]]|K02=Lock step mechanism of cyclic and contractile events|K03=[[T helper cell|T-helper cell type 2]] on site of injury}}
+{{Family tree| | | | | | | | K01 | | | | | |!| |,|-|'| | | | K02 | | | |!| | | | | K03 | K01=Recruitement of fibrocytes in [[lungs]]|K02=Lock step mechanism of cyclic and contractile events<ref name="pmid20427321">{{cite journal| author=Castella LF, Buscemi L, Godbout C, Meister JJ, Hinz B| title=A new lock-step mechanism of matrix remodelling based on subcellular contractile events. | journal=J Cell Sci | year= 2010 | volume= 123 | issue= Pt 10 | pages= 1751-60 | pmid=20427321 | doi=10.1242/jcs.066795 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20427321  }} </ref>|K03=[[T helper cell|T-helper cell type 2]] on site of injury}}
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 {{Family tree| | | | | | | | L01 | | | | | | L02 | | | | | | L03 | | | |!| | | | | L04 | |L01=Upregulation of [[CXCR4|C-X-C chemokine receptor type 4 (CXCR4)]]<br>on [[fibrocytes]] and its ligand<br>CXCL12 (stromal cell-derived factor 1)|L02=Excess extracellular matrix production|L03=Exerting traction force|L04=[[Interleukin-13]]}}
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-{{Family tree| | | | | | | | M01 | | | | | | M02 | | | | | | | | | | | |!| | | | | M03 | |M01=Migration of fibrocytes to the site of injury|M02=Tissue remodelling|M03=Alternate pathway activation of [[macrophages]]}}
+{{Family tree| | | | | | | | M01 | | | | | | M02 | | | | | | | | | | | |!| | | | | M03 | |M01=Migration of fibrocytes to the site of injury|M02=Tissue remodelling<ref name="pmid17525249">{{cite journal| author=Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G| title=The myofibroblast: one function, multiple origins. | journal=Am J Pathol | year= 2007 | volume= 170 | issue= 6 | pages= 1807-16 | pmid=17525249 | doi=10.2353/ajpath.2007.070112 | pmc=1899462 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17525249  }} </ref>|M03=Alternate pathway activation of [[macrophages]]}}
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