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Idiopathic pulmonary fibrosis (IPF) is a rare pulmonary disease caused by the formation of scar tissue in the lungs without any known triggering factor. Across the globe, five million people are affected with a prevalence slightly greater in men (20.2 out of every 100,000 vs. 13.2 in women). The average age at the time of diagnosis is 66 years. The average survival from the time of diagnosis is two to five years. [1]

IPF is marked by progressive fibrosis and respiratory insufficiency. It is considered a terminal disease and has a worse prognosis than many cancers. The theory of the pathogenesis of IPF has evolved from being an inflammatory disorder to being one marked by excessive fibroproliferation. While our understanding of this disease rapidly grows, as we learn more about the underlying cellular and molecular pathology, our prediction of a patient’s actual clinical course remains imperfect – many patients die without demonstrating a prior decline in their respiratory functioning. Some of these deaths may be explained by acute exacerbations, however, a good number occurred with no noted acute deteriorations. While some studies have demonstrated that a ten percent decline in forced vital capacity (FVC) predicted a worse prognosis, 43 percent of fatalities occurred despite not demonstrating such a decline in FVC. [2]

Some recent studies have demonstrated the importance of cell senescence playing a role in IPF. Cell senescence, which is characterized by cells being arrested in certain cycles, occurs due to a variety of stressors and is irreversible. These arrested cells release bioactive molecules, senescence-associated secretory phenotype (SASP) factors, which affect bystander cells. New evidence seems to show that extracellular vesicles (EVs) transfer various molecules – including microRNAs, messenger RNAs, DNA, and protein – that influence the communication between cells. EVs released from senescent cells appear to have unique characteristics leading to accelerated senescence (leading to inflammation), stem cell dysfunction, and cancer progression, similar to SASP factors. Several studies in pulmonary research seem to suggest EVs are an important factor in age-related lung disease. Interestingly, it has also been demonstrated that epithelial cells and fibroblasts, commonly seen in IPF, are known to accelerate cell senescence. [3]

For a long time, the role of alveolar macrophage-driven inflammation has been debated as an underlying pathogenic factor in IPF. A number of recent studies have examined bronchoalveolar lavage (BAL) using a variety of tests to evaluate for the production of cytokines and chemokines that have pro-inflammatory or fibrogenic activity. The results depending on the study reveal a number of chemokines with pro-inflammatory properties. In histiopathological and BAL studies in those with IPF, iron-laden macrophages were found to cluster in alveolar and interstitial spaces in patients with IPF. Researchers also noted increased capillary density, pulmonary veno-occlusive disease, microvasculitis, and pulmonary artery hypertension. [4]

One of the reasons it is so hard to diagnose IPF is the fact that the symptoms are so non-specific to the disease. A dry cough is reported in over 70 percent of patients and can be quite debilitating. This fact is interesting because the mechanism causing the cough is the result of afferent sensory fibers located in the central airways whereas, IPF is a disease of the peripheral parenchyma. In IPF, it is suggested that the mechanism of cough can be the result of altered neurophysiology and sensitization. An interesting observation found by researchers is that the cough in IPF may have an increased sensitivity to capsaicin, whose receptor is one of the family of transient receptor potential (TRP) belonging to the ion channels known as transient receptor potential vanniloid-1 (TRPV-1). Bronchial biopsies of IPF patients reveal a significant increase of TRPV-1 staining nerve profiles. [5]

Other researchers suggest that a communication error between endothelial cells and mesenchymal progenitors causing a switch to proremodeling phenotype. This switch modulates vascular regression as well as fibrosis. In PF, microvascular density (as determined by CD34+ cells) was found to be greater in angiogenesis in areas of remodeling as compared to normal lung tissue. It is unclear whether this is the result of reactive changes or whether it represents the heterogeneity of lesions that occur in the disease itself. Lymphangiogenesis is abnormal in patients with IPF and is an indicator of disease severity. [6]

In patients with familial IPF, mutations in surfactant genes or genes influencing telomere maintenance have been observed. Those patients who had mutations of telomere reverse transcriptase (TERT) or telomere RNA component (TERC) exhibited telomerase activity as well as prematurely shortened telomere length in blood leukocytes. Additionally, telomere length was shorter of the lung alveolar type 2 (AT2) in patients with IPF as compared with normal controls. It is unknown whether this is related to fibrosis. In a recent study in mice, it was found that telomere repeat binding factor-1 (TRBF-1)-deleted AT2 cells developed lung fibrosis. An interesting finding showed that patients with familial TERT mutation had shortened telomere lengths than patients with sporadic IPF. [7]

Clearly, the pathophysiology of IPF is quite complex with many factors playing a role in its development as well as prognosis. It is no longer just an inflammatory disease as scientists have believed for years. Cellular changes and genetic factors have been demonstrated to be involved in IPF. Despite out growing knowledge of histologic, immunologic and genetic factors contributing to IPF, prognosis remains poor and treatments limited. Perhaps, once we have refined our complete understanding of this disease we will be able to develop targeted treatments. Until then, doctors must be aware of clinical and radiologic factors of this disease. Current treatments need to better studied and new ones developed.

Want to learn more? You can find new Idiopathic Pulmonary Fibrosis CME on ResInsightsLive, and a program designed for patients and their families on RareDiseaseLive.

About the Author
Linda Girgis MD, FAAFP is a family physician practicing in South River, New Jersey. She was voted one of the top 5 healthcare bloggers in 2016. Follow her on twitter @DrLindaMD.

1- Meltzer EB, Noble PW. Idiopathic pulmonary fibrosis. Orphanet Journal of Rare Diseases. 2008;3(1):8. doi:10.1186/1750-1172-3-8.
2- Nathan SD, Noble PW, Tuder RM. Idiopathic Pulmonary Fibrosis and Pulmonary Hypertension. American Journal of Respiratory and Critical Care Medicine. 2007;175(9):875-880. doi:10.1164/rccm.200608-1153cc.
3- Wang W-J, Cai G-Y, Chen X-M. Cellular senescence, senescence-associated secretory phenotype, and chronic kidney disease. Oncotarget. 2017;8(38). doi:10.18632/oncotarget.17327..
4- Lee J, Arisi I, Puxeddu E, et al. Bronchoalveolar lavage (BAL) cells in idiopathic pulmonary fibrosis express a complex pro-inflammatory, pro-repair, angiogenic activation pattern, likely associated with macrophage iron accumulation. Plos One. 2018;13(4). doi:10.1371/journal.pone.0194803.
5- Hutchinson N-X, Gibbs A, Tonks A, Hope-Gill BD. Airway expression of Transient Receptor Potential (TRP) Vanniloid-1 and Ankyrin-1 channels is not increased in patients with Idiopathic Pulmonary Fibrosis. Plos One. 2017;12(11). doi:10.1371/journal.pone.0187847.
6- Kropski JA, Richmond BW, Gaskill CF, Foronjy RF, Majka SM. Deregulated angiogenesis in chronic lung diseases: a possible role for lung mesenchymal progenitor cells (2017 Grover Conference Series). Pulmonary Circulation. 2018;8(1):2045893217739807. doi:10.1177/2045893217739807.
7- Snetselaar R, van Batenburg AA, van Oosterhout MFM, et al. Short telomere length in IPF lung associates with fibrotic lesions and predicts survival. Zissel G, ed. PLoS ONE. 2017;12(12):e0189467. doi:10.1371/journal.pone.0189467.