The unrelenting and destructive progression of most fibrotic responses in the pulmonary, cardiovascular, integumentary, and alimentary systems remains a major medical challenge for which therapies are desperately needed. The pathophysiology of fibrosis remains an enigma, but considerable research and debate surrounds the question of whether chronic inflammation is the key driver of unrestrained wound healing (i.e., the fibrotic response) in these and other organ systems. This Review describes how infectious pathogens, chronic inflammation, and unrestrained fibroproliferation are likely to be part of a dynamic, unrelenting process propelling human fibrotic diseases.

Idiopathic pulmonary fibrosis is a generally progressive disorder with highly heterogeneous disease progression. The most common of the idiopathic interstitial pneumonias, idiopathic pulmonary fibrosis is characterized by a steady worsening of lung function and gas exchange cause by diffuse alveolar damage and severe fibrosis. We examined clinical features of patients with idiopathic pulmonary fibrosis to classify them as exhibiting rapid or slowly progressive over the first year of follow-up. We identified differences between the two groups in order to investigate the mechanism of rapid progression. Previous work from our laboratory has demonstrated that Toll-like receptor 9, a pathogen recognition receptor, promotes myofibroblast differentiation in lung fibroblasts cultured from biopsies of patients with idiopathic pulmonary fibrosis. Therefore, we hypothesized that TLR9 functions as both a sensor of pathogenic molecules and a profibrotic signal in rapidly progressive idiopathic pulmonary fibrosis. TLR9 was present at higher concentrations in surgical lung biopsies from rapidly progressive patients than in tissue from normal controls. Fibroblasts from rapid progressors were more responsive to the TLR9 agonist, CpG, than were fibroblasts from control patients. We used a humanized SCID mouse and demonstrated that there was increased fibrosis in murine lungs receiving human lung fibroblasts from rapid progressors than in mice receiving normal fibroblasts. This fibrosis was exacerbated by intranasal CpG challenges. Furthermore, CpG induced the differentiation of blood monocytes into fibrocytes and the epithelial-to-mesenchymal transition of A549 lung epithelial cells. These data suggest that TLR9 may drive the pathogenesis of rapidly progressive idiopathic pulmonary fibrosis and is a potential indicator of this subset of the disease.

In the last few years, a number of reports have clearly shown that pulmonary T lymphocytes have evolved a number of effector mechanisms to respond to foreign antigens, ranging from direct cytotoxicity mechanisms to secretion of lymphokines, that have the ability to activate themselves or other pulmonary immunocompetent cells. Furthermore, there is also evidence that lung T cells may have a role in the immunopathogenetic mechanisms taking place in the lung of most immune-mediated diffuse lung disorders. In this paper, we will review the current concepts on the recruitment, homing, and activity of T lymphocytes in the lower respiratory tract of patients with sarcoidosis. The relevant phenotypic and functional abnormalities detected on T cells in sarcoidosis will be discussed. Furthermore, we will comment recent findings on the ability of immunomodulatory molecules, such as proinflammatory cytokines, chemokines, and other cytokines, to regulate T-cell function in immune mechanisms leading to granuloma formation and maintenance.

Infectious diseases can be cofactors in idiopathic interstitial pneumonias (IIP) pathogenesis; recent data suggests that toll-like receptors 9 (TLR9) ligands contribute to experimental chronic tissue remodeling. Real-time TAQMAN and immunohistochemical analysis of IIP normal surgical lung biopsies (SLBs), primary fibroblast lines grown from both IIP and normal SLBs indicate that TLR9 is prominently and differentially expressed in a disease-specific manner. TLR9 expression was increased in biopsies from patients with IIP compared with normal lung biopsies and its expression localized to areas of marked interstitial fibrosis. TLR9 in fibroblasts appeared to be increased by profibrotic Th2 cytokines (IL-4 and IL-13) and this was true in fibroblasts cultured from the most severe form of IIP, idiopathic pulmonary fibrosis (IPF) SLBs, in non-specific interstitial pneumonia fibroblast lines, and in normal fibroblasts. Finally, confocal microscopy studies have shown that TLR9 activation by its synthetic agonist CpG-ODN significantly increased the expression of alpha smooth muscle actin, the main marker of myofibroblast differentiation. These data indicate that TLR9 expression may drive the abnormal tissue healing response in severe forms of IIP and its activation can have a key role in myofibroblast differentiation promoting the progression of disease during the terminal phase of IPF.

We report a rare case of an incidental diagnosis of necrotizing sarcoid granulomatosis (NSG) in a 60-y-old non-smoking male. The patient was admitted to the hospital for sudden back pain. Chest x-ray revealed areas of parenchymal consolidation and high-resolution computed tomography demonstrated a pulmonary nodular pattern with no lymph node enlargement. All laboratory and pulmonary function tests were normal. Bronchoscopy with bronchoalveolar lavage showed no sign of infection or specific inflammation. The diagnosis of NSG was made by histopathological examination of a surgical lung biopsy and by excluding other causes of granulomatous disease. In paucisymptomatic/asymptomatic patients, as in our case, therapy is not necessary, with a good prognosis and complete recovery. NSG is a rare systemic disease similar to sarcoidosis and Wegener's granulomatosis with a benign clinical course and should always be considered for patients with nodular pulmonary lesions even with subclinical or uncommon features.