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Offered alternative pathogenesis theories and further elaborated on said possible mechanisms and their implications to research and treatments for the disease. |
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IPF is believed to be the result of an aberrant wound healing process including/involving abnormal and excessive deposition of [[collagen]] (fibrosis) in the [[pulmonary interstitium]] with minimal associated [[inflammation]].<ref name=HarariCaminati>{{cite journal |vauthors=Harari S, Caminati A | title = IPF: new insight on pathogenesis and treatment | journal = Allergy| volume = 65 | issue = 5 | pages = 537–553 | year = 2010 | pmid = 20121758 | doi = 10.1111/j.1398-9995.2009.02305.x| s2cid = 21633787 }}</ref> [[Cellular senescence]] is suspected to be a central contributing cause, a belief which is supported by benefits seen in patients given [[senolytic]] therapy.<ref name="pmid30616998">{{cite journal | vauthors = Justice JN, Nambiar AM, Tchkonia T, Kirkland JL | title = Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study | journal = [[EBioMedicine]] | volume = 40 | pages = 554–563 | date=2019 | url= | doi = 10.1016/j.ebiom.2018.12.052 | pmc=6412088 | pmid = 30616998}}</ref><ref name="pmid31451866">{{cite journal | vauthors = Palmer AK, Gustafson B, Kirkland JL, Smith U | title = Cellular senescence: at the nexus between ageing and diabetes | journal = [[Diabetologia]] | volume = 62 | issue=10 | pages = 1835–1841 | date=2019 | url= | doi = 10.1007/s00125-019-4934-x | pmc=6731336 | pmid = 31451866}}</ref><ref name="pmid32686219">{{cite journal | vauthors = Kirkland JL, Tchkonia T| title = Senolytic Drugs: From Discovery to Translation | journal = [[Journal of Internal Medicine]] | date=2020 | volume = 288 | issue = 5 | pages = 518–536 | doi = 10.1111/joim.13141 | pmid = 32686219| pmc = 7405395 | doi-access = free }}</ref>
It is hypothesized that the initial or repetitive injury in IPF occurs to the lung cells, called alveolar epithelial cells (AECs, pneumocytes), which line the majority of the alveolar surface.<ref name=LoomisFlaherty>{{cite journal |vauthors=Loomis-King H, Flaherty KR, Moore BB | title = Pathogenesis, current treatments and future directions for idiopathic pulmonary fibrosis | journal = Current Opinion in Pharmacology| volume = 13 | issue = 3 | pages = 377–385 |date=April 2013 | pmid = 23602652| pmc = 3686907| doi = 10.1016/j.coph.2013.03.015}}</ref> When type I AECs are damaged or lost, it is thought that type II AECs undergo proliferation to cover the exposed [[basement membrane]]s. In normal repair, the hyperplastic type II AECs die and the remaining cells spread and undergo a differentiation process to become type I AECs. Under pathologic conditions and in the presence of [[transforming growth factor beta]] (TGF-β), [[fibroblasts]] accumulate in these areas of damage and differentiate into [[myofibroblasts]] that secrete collagen and other proteins.<ref name=LoomisFlaherty /> In the current classification of the pathogenesis of IPF, it is believed that it occurs by way of the formation of a UIP (usual interstitial pneumonia) lesion, which then undergoes the aforementioned pathological condition characteristic of IPF.<ref>{{Cite journal|
In the past, it was thought that [[inflammation]] was the first event in initiating lung tissue scarring. Later findings showed that the development of fibroblastic foci precedes the accumulation of inflammatory cells and the consequent deposition of collagen.<ref name="PardoSelman">{{cite journal |vauthors=Pardo A, Selman M | title = Idiopathic pulmonary fibrosis: new insights in its pathogenesis | journal = The International Journal of Biochemistry & Cell Biology| volume = 34 | issue = 12 | pages = 1534–1538 | year = 2002 | pmid = 12379275| doi = 10.1016/s1357-2725(02)00091-2}}</ref> This pathogenetic model is indirectly supported by the clinical features of IPF, including an insidious onset over several years, relatively infrequent acute exacerbations, and failure to respond to [[immunosuppressive therapy]].<ref name="HarariCaminati" /><ref name="SelmanKing">{{cite journal |vauthors=Selman M, King TE, Pardo A | title = Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy | journal = Annals of Internal Medicine| volume = 134 | issue = 2 | pages = 136–151 | year = 2001 | pmid = 11177318 | doi = 10.7326/0003-4819-134-2-200101160-00015| s2cid = 10955241 }}</ref> However, it is the belief of some researchers that the disease is a multi-mechanistic one, wherein the trigger for the disease may stem from abnormalities in any number of wound healing pathways, including the inflammatory response.<ref name=":0" /> Such abnormalities could occur in any number of the nine implicated pathways (clotting cascade, antioxidant pathways, apoptosis, inflammatory cytokines, angiogenesis and vascular remodelling, growth factors, surfactant and matrix regulatory factors)<ref name=":0" />, and that through further investigation into all nine, novel therapies and approaches could be proposed on a unique or case by case basis should attempts at treating or circumventing complications in any one pathway prove unsuccessful. A number of therapies that target fibroblast activation or the synthesis of extracellular matrix are currently in early testing or are being considered for development.{{cn|date=November 2020}}
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