**6.1. Classic mechanisms in the pathogenesis of interstitial pneumonia in connective tissue disease**

known as CCN2, which plays a pivotal role in the stimulation of extracellular matrix production and myofibroblast differentiation, is involved in angiogenesis and forming the connective tissue [143]. The levels are elevated in the skin and lungs from SSc patients as well as in

Interstitial Pneumonia Associated with Connective Tissue Disease: A Comprehensive…

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The earliest events of the parenchymal lung involvement in CTD include inflammation and associated alveolar epithelial injury which occurs due to undetermined causes or can be caused by some environmental pathogens. The alveolar epithelial damage and inflammation let resident fibroblasts of pulmonary interstitium to locate to the alveolar wall, and the fibroblasts become activated through a variety of mediators such as TGF-β [145, 146]. The activation of resident fibroblasts was shown to be induced by the recruitment of active TGF-β from the lung tissue [147]. The resident lung fibroblasts play a pivotal role in lung fibrosis, and they are considered to be a more primitive or less differentiated lineage of fibroblasts that are prepared for repair at injury response [148]. The recruitment of activated fibroblasts and myofibroblasts that produce large amount of extracellular matrix proteins occurs in the process. These population of cells are not only derived from resident interstitial fibroblasts but also come from circulating progenitor cells which include mesenchymal stem cells recruited from the bone marrow and cells of a monocyte lineage that localize to the lung [149]. Myofibroblasts persist as critical profibrotic cells in affected lung tissue. It is conceivable that minor injury and subsequent disease process lead to the development of a lung microenvironment prone to fibrosis. That series of events results in an accumulation of constituents of the extracellular matrix (ECM), which remodels normal tissue architecture, which in turn culminates in pulmonary organ failure. Essentially, the lung is primed to develop fibrosis in response to injury, and it is likely that the intrinsic response is more severe in CTDs than normal individuals. Thus, in SSc, such genetic or intrinsic differences can be reflected to the serological phenotypes such as the expression of autoantibodies. Patients with SSc having anti-topoisomerase antibodies are liable to develop significant lung fibrosis, while those with

the sera [144].

anti-RNA polymerase III antibodies are less [150].

*6.1.2. Involvement of immune mechanisms in interstitial pneumonia in systemic sclerosis*

The immune system is also implicated in the pathology of SSc. Several lines of evidence suggest that a specific population of activated T cells exhibiting type 2 helper T (Th2) phenotype potentially mediates tissue fibrosis, secreting IL-4 and IL-13 both of which activate fibroblasts and collagen production by inducing TGF-β [151]. In SSc, T cells with memory phenotype were found in lung biopsy specimens from patients with lung involvement [152]. In some studies reported, increased numbers of lung memory CD8 T cells are associated with more severe pulmonary fibrosis [153–155]. Luzina et al. have shown an increase in CD8 T cells in the lungs of SSc patients by using T cells isolated from BAL fluid and demonstrated that a subset of patients at higher risk of progressive lung disease had activated, long-lived CD8 T cells which could promote fibrosis through production of profibrotic factors such as IL-4 and oncostatin M, as well as activation of TGF-β [156]. Regulatory T cells (Tregs) which maintain self tolerance can be impaired in their ability to suppress CD 4 effector T cells [157]. Currently, the precise knowledge of the role of effector cells in innate and adaptive immune system in

Numbers of studies on the pathogenesis of IP have been performed in SSc as well as in mouse models of IP, providing evidence for plausible mechanisms that may lead to pulmonary fibrosis in CTD. This is natural because, among the whole CTDs, SSc has the highest prevalence of IP, and currently, the lung disease consists the major cause of death in patients with SSc, being shifted away from mortality due to renal crisis which was more common in the past. The high morbidity and mortality due to IP in SSc have been eliciting not only multidisciplinary clinical studies but also basic researches. Many lines of evidence acquired from the studies on SSc, and relevant researches on fibrosis have been implying the following potential scenario of classic mechanisms in the pathogenesis of CTD-IP [12, 132, 133].
