Interstitial lung diseases (ILDs) are a heterogeneous group of pathologies that affect the lung parenchyma with wide inflammation and diffuse fibrosis
[1]. Fibrotic ILDs cause the onset of progressive symptoms in patients that culminate in the decline of lung functions and often respiratory failure, which translates to a poor quality of life for patients. Interstitial lung diseases are a broad spectrum of lung pathologies that can be divided into two groups: ILDs with a known cause and ILDs without a known cause that give rise to the idiopathic form of pulmonary fibrosis
[2][3]. Furthermore, the possible causes of the ILDs identified are represented by systemic diseases such as connective tissue disease
[4][5] or environmental exposure to pneumotoxic drugs
[6], radiation therapy
[6], occupational exposures (e.g., asbestosis)
[7] or allergens in the case of hypersensitivity pneumonitis
[8]. The discrimination among different ILDs that present hetherogeneous inflammatory and fibrotic patterns even among patients with the same disease is critical for a more predictable prognosis and a more efficient management of the patients. Among ILDs, idiopathic pulmonary fibrosis (IPF) is the most common and severe, and for this reason the distinction between IPF and non-IPF ILDs is important given the poor prognosis in IPF compared to other fibrosing ILDs
[9]. Idiopathic pulmonary fibrosis represents the most common form of idiopathic interstitial pneumonia (IIP) and is characterized by the progressive remodeling of the lung parenchyma structure, which exaggerates extracellular matrix deposition and irreversible scarring. IPF occurs primarily in older adults, with a median survival of 3 years after diagnosis, and it is diagnosed by clinicopathological criteria, including the radiographic and/or histological hallmark pattern of usual interstitial pneumonia (UIP)
[10]. Prognosis remains extremely poor, since most patients die for progressive respiratory failure, often precipitated by acute events, namely, disease exacerbations
[11]. Indeed, since the natural history and the course of the disease is variable among patients, the prognosis could be quite unpredictable
[12]. Despite the recent introduction of the two antifibrotic drugs, namely, pirfenidone and nintedanib, that can slow down the respiratory functional decline of IPF patients according to both the real-word data and randomized controlled trials, such as CAPACITY and ASCEND, where they improved survival in patients, IPF still has a high mortality rate and survival times are quite heterogenous
[3][13][14][15]. Besides the IPF, the IIPs include the non-specific interstitial pneumonia (NSIP), which is an interstitial lung disease that may be both idiopathic and secondary to connective tissue disease, toxins or other causes
[16], cryptogenic organizing pneumonia (COP), also known as bronchiolitis obliterans organizing pneumonia (BOOP), that has been hypothesized to be secondary to alveolar epithelial injury due to an unknown insult, acute interstitial pneumonia (AIP) that is an extremely severe idiopathic acute interstitial disease
[17], desquamative interstitial pneumonia (DIP), which is strongly associated with smoking, respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), characterized by the combination of interstitial disease and respiratory bronchiolitis, and lymphocytic interstitial pneumonia (LIP) that in the majority of patients is associated with systemic autoimmune or immunodeficiency disorders, including connective tissue diseases, or in rare cases can be idiopathic
[18]. The most updated version of the guidelines concerning the IIPs from the American Thoracic Society/European Respiratory Society (2013)
[19] introduced some changes regarding the classification of these diseases compared to the original classification (2002)
[20]. In particular, the IIPs are divided into four main groups (chronic fibrosing, smoking-related, acute/subacute, and rare) with the addition of a new disease: idiopathic pleuro parenchymal fibroelastosis
[1]. Most of the ILDs have unknown etiology while there are a group of ILDs related/due to occupational and environmental exposure
[21][22][23]. Although the majority of the ILDs can have unknown etiology, different works suggest that environmental factors could represent a risk factor in ILDs such as IPF since they may increase the probability of developing the disease in genetically susceptible individuals. In particular, according to the current integral model, the fibrotic pathway in IPF patients is activated by recurrent alveolar epithelium injury (e.g., environmental risks) that, together with compromised repair mechanisms of alveolar epithelium, leads to the initiation, development and progression of the disease
[24][25][26]. Thus, the alveolar epithelial cells (AECs) are unable to properly respond to repetitive injuries, resulting in the loss of epithelial integrity that, together with the secretion of pro-fibrotic factors, represents the initial crucial mechanism of IPF development promoting fibroblast migration, proliferation, activation and differentiation into myofibroblasts with deposition of Extracellular Matrix (ECM) and the following distortion of the lung architecture. From a macroscopic point of view, these processes cause an increase in the stiffness of the pulmonary parenchyma, leading to the impairment of gas exchange in the alveolar district. Since the epithelial cells represent the initiator of the pulmonary fibrosis and the myofibroblasts are the key effector cells that orchestrate the progression of the disease, several recent studies aiming to clarify the molecular mechanism behind the IPF progression are focused on the identification of the cellular origin of myofibroblast. Initially, different works connected the cellular identity for the myofibroblasts origin to resident lung fibroblasts able to directly differentiate into myofibroblasts under profibrotic stimuli
[27], epithelial cells undergoing mesenchymal transition, namely, epithelial–mesenchymal transition (EMT)
[28][29], bone marrow (BM)-derived cells as circulating fibrocytes
[30] and pericytes
[31][32]. Lately, the contribution of the epithelial cells through the EMT and the circulating fibrocytes have been objects of several debates
[33][34] to such an extent that they are not considered to be cells giving rise to myofibroblasts. To date, given the results obtained from cell-lineage tracing experiments using reporter mouse models, four different cellular types have been demonstrated to acquire the myofibroblastic phenotype
[35]. Among them, we found the following: interstitial lung fibroblasts localized in the interstitium immediately adjacent to alveolar epithelial cells
[33], lipofibroblasts located near the AECs are lipid-droplet-containing interstitial fibroblasts
[35], pericytes within the capillary basement membrane
[36], mesothelial cells from pleural-mesothelium that line the visceral and parietal pleural surfaces
[37], and resident lung mesenchymal progenitors, whose contribution in the myofibroblast-differentiating process seems prevalent
[38]. Since it has been demonstrated that non-IPF ILD may display a progressive phenotype as IPF, opening the possibility to explore the use of antifibrotic drugs for the non-IPF patients, and given the positive outcomes from this, we could speculate that different ILDs may share a similar molecular mechanism that culminates in the fibrogenic phenotype
[39][40]. Indeed, since the interstitial lung disease can include rare, heterogeneous and poorly understood diseases, their classification, the identification of the different subtypes, an accurate diagnosis and the prediction of disease progression could be challenging for the clinicians
[41].