IPF is a disorder of progressive course with fatal complications. The etiology and pathogenesis of this disease are still unclear [8]. The development and progression of IPF have been strongly related to activation of lung fibroblast and epithelial cell, as well as fibrotic and inflammatory mediators secretion [10].
This study revealed that the most prevalent clinical complaints, such as dry cough and marked dyspnea, were significantly increased in IPF patients. Regarding pulmonary function tests, the patients in the present study are distinguished by restrictive lung disease patterns (FVC% of predicted and DLCO). These findings were expected because of the nature of interstitial lung diseases.
Non-coding RNAs, including lncRNAs with a length of over 200 nucleotides, are the major transcription products in mammalian cells. Although several studies have started to clarify lncRNA function in human diseases, lncRNA expression profiles, as well as roles in IPF, remain unclear.
Herein, a PCR-based method was utilized to evaluate the TERRA expression level in peripheral blood of IPF patients. Although there have not been many studies conducted on TERRA expression in IPF, we found that increased TERRA expression is significantly related to an increase in IPF incidence. This is consistent with the findings of Gao et al. [7] who demonstrated that an increase in TERRA expression levels of IPF patients, along with its association with dysfunction of telomeres caused by oxidative stress, contributes to IPF pathogenesis.
Cao et al. [11] identified a large number of lncRNAs with altered expression in rat lungs using experimental fibrosis. They showed differences in the RNA component of mitochondrial RNA processing endoribonuclease expression in addition to telomere enzyme RNA component (Terc) in a bleomycin-induced fibrotic murine model. This was the first piece of evidence that suggests participation of lncRNAs in pathogenesis of pulmonary fibrosis. Moreover, pulmonary fibrosis can be induced by destructing CCAAT box in lncRNA Terc promoter [12]. Besides, Liu et al. [13] demonstrated that lncRNA telomerase reverse transcriptase (Tert) inactivation reduces the pulmonary fibrosis severity in mice exposed to conditional knockout.
Much evidence proposed that lncRNAs have a role in cell proliferation. The residential lung fibroblast proliferation represents one of the leading providers that increase IPF fibroblastic foci [14]. Certain lncRNAs, namely LINC00960 and LINC01140, were suggested to be upregulated, and LINC01140 knockdown but not LINC00960 leads to stimulation of inflammatory response fibroblasts in IPF. As a result, this demonstrated the necessity of lncRNAs as both proliferation and inflammation regulators in IPF [15]. Besides, Dai et al. [16] found that MALAT1 in rat models was activated by the inflammatory response pathway caused by lipopolysaccharide and promoted lung injury progression.
Numerous researches indicate different functions of lncRNAs like acting as miRNA sponges, or decoys, holding a role as competitive endogenous RNAs for microRNAs, and having importance in physiological as well as pathological events. Nevertheless, expression profiles, as well as lncRNA roles in IPF, remain unclear [14].
In the case of patients that have newly identified interstitial lung diseases (ILD) and possess an HRCT scan pattern of a UIP, they were strongly recommended against conducting surgical lung biopsy, transbronchial lung biopsy, in addition to lung cryobiopsy. Besides, a conditional recommendation was made to conduct BAL after excluding other existing ILD causes (like domestic and occupational environmental exposures, connective tissue diseases, and drug toxicity) [3].
Our study showed a predominance of reticulation and honeycombing in HRCT equivalent to that observed in a study by Kono et al. [8] in which HRCT score inter-observer agreement was good, and the honeycombing and reticulation extent scores were significantly higher in IPF than in non-IPF idiopathic interstitial pneumonia.
The results indicated a significant positive correlation between patient’s age and TERRA expression levels. In addition, a progressive shortening of telomere length is commonly associated with cellular senescence. The lncRNA TERRA suppresses telomere elongation and modulates telomeric heterochromatin by linking with multiple telomeric proteins: repeat factor telomere (TRF1, TRF2), origin-recognition complex (ORC), and the H3K9me3 factor [17].
Hao et al. [18] demonstrated that patients with IPF demonstrated a remarkable increase of lncRNA AP003419.16 expression and its adjacent gene, RPS6KB2, and this may lead to increased risk of aging-associated IPF. Previous data suggested that lncRNAs are involved in regulating aging-associated disease [19] and aging pathways [20].
In this study, TERRA expression levels were inversely correlated with FVC% of predicted and directly correlated with HRCT reticular extent score. Lung biopsy is considered important as the only strategy that can give an accurate diagnosis for IPF. Furthermore, a biopsy of the lungs is an invasive procedure resulting in increased morbidity as well as mortality risks. TERRA research remains at an early stage, and the emphasis on TERRA research to find suitable therapies will continue to evolve in the future.