Fibrotic Idiopathic Interstitial Lung Disease: The Molecular and Cellular Key Players

Abstract

Interstitial lung diseases (ILDs) that are known as diffuse parenchymal lung diseases (DPLDs) lead to the damage of alveolar epithelium and lung parenchyma, culminating in inflammation and widespread fibrosis. ILDs that account for more than 200 different pathologies can be divided into two groups: ILDs that have a known cause and those where the cause is unknown, classified as idiopathic interstitial pneumonia (IIP). IIPs include idiopathic pulmonary fibrosis (IPF), non-specific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP) known also as bronchiolitis obliterans organizing pneumonia (BOOP), acute interstitial pneumonia (AIP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), and lymphocytic interstitial pneumonia (LIP). In this review, our aim is to describe the pathogenic mechanisms that lead to the onset and progression of the different IIPs, starting from IPF as the most studied, in order to find both the common and standalone molecular and cellular key players among them. Finally, a deeper molecular and cellular characterization of different interstitial lung diseases without a known cause would contribute to giving a more accurate diagnosis to the patients, which would translate to a more effective treatment decision.

Cell-Specific Response of NSIP- and IPF-Derived Fibroblasts to the Modification of the Elasticity, Biological Properties, and 3D Architecture of the Substrate

“…Disorders in ECM composition, especially the high abundance of collagen, may also affect the mechanical properties of the tissue, leading to its stiffening. Although the impact of tissue elasticity on lung fibroblasts has already been studied [ 48 , 52 , 53 , 54 ], the effect of simultaneous modification of mechanical and biological properties of the environment, which, in fact, is more suitable for the fibrotic process in lung tissue, has not been examined extensively. This issue deserves attention, since the interactions with biologically modified substrates of different elasticities should differ for the examined cell lines, providing a potential tool to discriminate between them.…”

“…On the nanoscopic scale, the subcellular mechanisms are mainly affected, while on the microscopic scale, the topography of the substrate impacts the whole cell behaviors, such as cell morphology [ 88 , 89 , 96 ]. For lung fibrosis, the homogeneous porous architecture of normal lung tissue changes due to the fibrotic process into a honeycomb pattern [ 53 , 62 , 97 , 98 ]; therefore, the topography on the microscopic scale could also be a factor that impacts the behavior of fibroblasts derived from IPF and NSIP differently. To study this issue, 3D PDMS substrates were prepared using two approaches, based on the addition of soluble particles to the PDMS mixture or their molding with a predefined master, and used as substrates for the culture of IPF- and NSIP-derived fibroblasts, as well as healthy fibroblasts.…”

“…In turn, disorders in the biochemical composition of the lungs, especially pathological accumulation of collagen and cholesterol [ 26 , 28 , 45 , 46 ] lead to increased tissue stiffness and influence the contractile and proliferative functions of lung fibroblasts, which can result in the transformation of fibroblasts into myofibroblasts [ 24 , 27 , 36 , 39 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ]. The impact of matrix elasticity on the development of IPF has already been examined [ 48 , 52 , 54 , 55 ], though analogous research for NSIP-derived cells is very rare [ 56 ].…”

Molecular Mechanisms and Cellular Contribution from Lung Fibrosis to Lung Cancer Development

“…The onset and progression of IPF leads to massive changes in the architecture of lungs and their biomechanical properties that often culminate in respiratory failure due to the impairment of alveolar gas-exchange and the decline of lung functions [2,3]. Although the diagnosis of IPF can be extremely challenging due to the heterogenous nature of this disease [4], it is recognized by clinicopathological criteria, including the radiographic and histological hallmarks pattern of usual interstitial pneumonia (UIP) [5]. Currently, there are two antifibrotic drugs used as a therapeutic strategy for IPF patients, Pirfenidone and Nintedanib, that are able to slow down the respiratory functional decline and improve survival in IPF patients [6][7][8].…”

Mesenchymal Stromal Cells for the Treatment of Interstitial Lung Disease in Children: A Look from Pediatric and Pediatric Surgeon Viewpoints

“…Stem cell therapy represents a prospective approach in regenerative medicine for the repair, replacement, and rejuvenation of tissue [ 1 , 2 ]. Mesenchymal stromal cells (MSCs) expanded in vitro have been proposed as potential therapy to treat congenital and acquired lung diseases [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ].…”