Idiopathic Pulmonary Fibrosis (IPF)


Idiopathic pulmonary fibrosis (IPF) is a rare interstitial lung disease characterized by progressive fibrosis leading to symptoms of chronic cough, dyspnea, and decreased lung function that is often fatal.1 The prognosis for patients with IPF is generally poor, and median survival times after diagnosis are generally 3-5 years without treatment.1 Despite the poor prognosis, the clinical course of the disease can be quite variable, with some patients experiencing rapid decline while others encounter a much slower progression.2 An estimated 10% to 20% of patients may experience acute exacerbations that often lead to hospitalization and a high mortality rate.2

IPF has been described in the English-language literature since at least the mid-1900s.3 These papers led to more widespread awareness of the disease and have resulted in research into the possible causes. Although many discoveries have been made and several theories of pathophysiology exist, the exact cause of IPF is still unknown. However, a number of factors have been identified that may increase a patient’s risk of acquiring the disease.

Pathophysiology

Idiopathic Pulmonary Fibrosis Etiology
Credit: National Heart, Lung, and Blood Institute

The exact causation and pathophysiology of IPF are currently unknown. It is believed that IPF begins with repeated injury to the alveolar epithelial cells (AECs) followed by dysregulation somewhere in the wound repair process, leading to excessive accumulation of scar tissue.4,5 These initial repeated injuries are believed to be caused by chronic exposure to irritants such as cigarette smoke, dust, or infectious agents that damage the delicate cells of the alveolar lining.4

In normal conditions after injury, coagulation and inflammatory cascades are activated to stop bleeding and deal with foreign matter or microbes. Fibroblasts are then activated and recruited to proliferate and rebuild extracellular matrix (ECM) compounds to begin repair. Finally, a remodeling stage restores normal tissue integrity and structure.5 

Evidence has shown that certain types of AECs may be involved in the pathophysiology of IPF. Most of the alveolar surfaces are lined with type 1 AECs, which are involved in the normal functioning of the lungs. Injury to these cells leads to hyperplasia of type 2 surfactant-producing AECs in order to protect the lungs.5 If injury continues or there is dysfunction in the process of reestablishing normalcy and type 1 AECs, possibly through genetic causes, the tissue enters an inflammatory phase.4 During this phase, AECs are believed to release profibrotic cytokines, growth factors, and chemokines that lead to proliferation of fibroblasts and myofibroblasts, resulting in an abnormally thick and stiff ECM.5 Abnormalities in any of these processes may also cause abnormal fibrosis.

Risk Factors

Several factors have been identified that can increase a patient’s risk of IPF, including advanced age, exposure to lung irritants, genetics, and gender.

Age

One major risk factor for IPF is patient age, with most cases being diagnosed after age 50 and an increased incidence as people age.6 Research has shown a correlation between age and IPF, and a number of different possible mechanisms have been proposed linking the two.7 People of a more advanced age may have more previous exposure to environmental factors and reactive oxygen species, a weakened immune system, more epigenetic modifications, an increased number of mutations due to cellular reproduction, shortening of telomeres, higher apoptosis, less stable stem cells, and possible dysregulation of autophagy that could all play a part in the development of IPF.7 Alterations in age-related mitochondrial functions such as mitochondrial energetics, preservation and repair of mitochondrial DNA, biogenesis, and mitophagy have also been seen in endothelial cells, macrophages, and fibroblasts of patients with IPF.8

Exposure to Irritants

Exposure to several different lung irritants have been shown to be possible risk factors for initiating IPF through repeated lung epithelial damage. The most strongly associated risk factor for IPF is cigarette smoking,2 which may cause continued epithelial irritation even after smoking cessation.4 Several different varieties of dusts, including metal, wood, stone, sand, and silica, have also been correlated with an increased risk of IPF.4 Working in agriculture and farming, as well as with livestock, have also been shown to increase the risk of IPF.9

Gastroesophageal reflux disease (GERD) has a high prevalence in patients with IPF, estimated to be between 87% and 94%,9 and may cause IPF through chronic aspirations or microaspirations of gastric fluids.2 A number of microbial agents may also be risk factors for IPF. Chronic viral infections including hepatitis C, Epstein-Barr virus, cytomegalovirus, and human herpesvirus-8 have also been found in the lungs of patients with IPF, although it is unclear if they are causative or merely comorbidities.4  

Genetics

A number of genetic factors may increase the risk of developing IPF. Mutations in genes related to the epithelial cell-cell adhesion molecules including DSP and DPP9; alveolar surfactant protein production and secretion such as SFTPC, SFTPA1, and SFTPA2; cell senescence including TERT, TERC, DKC1, PARN, and RTELI; mucus production such as MUC5B; and host defense including genes related to the human leukocyte antigen region on chromosome 6p21.31 may cause dysfunction of the wound healing process after exposure to lung irritants.10 Epigenetic changes including DNA methylation4 and expression of non-coding RNAs including microRNAs and long non-coding RNAs are likely also involved in IPF development.5

Gender

Some studies have shown that men are at a higher risk of developing IPF than women.11 This may be due to men being more likely to smoke or be involved in professions that would expose them to lung irritants. More recent studies argue that at least some of the differences may be related to physician bias, leading to an underdiagnosis of IPF in women and an overdiagnosis in men.12

References

  1. Quinn C, Wisse A, Manns ST. Clinical course and management of idiopathic pulmonary fibrosis. Multidiscip Respir Med. 2019;14:35. doi:10.1186/s40248-019-0197-0
  2. Sauleda J, Núñez B, Sala E, Soriano JB. Idiopathic pulmonary fibrosis: epidemiology, natural history, phenotypes. Med Sci (Basel). 2018;6(4):110. doi:10.3390/medsci6040110
  3. Homolka J. Idiopathic pulmonary fibrosis: a historical review. CMAJ. 1987;137(11):1003-1005.
  4. Sgalla G, Iovene B, Calvello M, Ori M, Varone F, Richeldi L. Idiopathic pulmonary fibrosis: pathogenesis and management. Respir Res. 2018;19(1):32. doi:10.1186/s12931-018-0730-2
  5. Hadjicharalambous MR, Lindsay MA. Idiopathic pulmonary fibrosis: pathogenesis and the emerging role of long non-coding RNAs. Int J Mol Sci. 2020;21(2):524. doi:10.3390/ijms21020524
  6. Gulati S, Thannickal VJ. The aging lung and idiopathic pulmonary fibrosis. Am J Med Sci. 2019;357(5):384-389. doi:10.1016/j.amjms.2019.02.008
  7. Leung J, Cho Y, Lockey RF, Kolliputi N. The role of aging in idiopathic pulmonary fibrosis. Lung. 2015;193(4):605-610. doi:10.1007/s00408-015-9729-3
  8. Zank DC, Bueno M, Mora AL, Rojas M. Idiopathic pulmonary fibrosis: aging, mitochondrial dysfunction, and cellular bioenergetics. Front Med (Lausanne). 2018;5:10. doi:10.3389/fmed.2018.00010
  9. Wakwaya Y, Brown KK. Idiopathic pulmonary fibrosis: epidemiology, diagnosis and outcomes. Am J Med Sci. 2019;357(5):359-369. doi:10.1016/j.amjms.2019.02.013
  10. Kaur A, Mathai SK, Schwartz DA. Genetics in idiopathic pulmonary fibrosis pathogenesis, prognosis, and treatment. Front Med (Lausanne). 2017;4:154. doi:10.3389/fmed.2017.00154
  11. Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006;174(7):810-816. doi:10.1164/rccm.200602-163OC
  12. Assayag D, Morisset J, Johannson KA, Wells AU, Walsh SLF. Patient gender bias on the diagnosis of idiopathic pulmonary fibrosis. Thorax. 2020;75(5):407-412. doi:10.1136/thoraxjnl-2019-213968

Reviewed by Harshi Dhingra, MD, on 7/1/2021.

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