Idiopathic pulmonary fibrosis (IPF) is a devastating disease, with a median survival as short as 3 years from the time of diagnosis and no pharmacological therapies yet approved by the U.S. Food and ...Drug Administration. To address the great unmet need for effective IPF therapy, a number of new drugs have recently been, or are now being, evaluated in clinical trials. The rationales for most of these therapeutic candidates are based on the current paradigm of IPF pathogenesis, in which recurrent injury to the alveolar epithelium is believed to drive aberrant wound healing responses, resulting in fibrosis rather than repair. Here we discuss drugs in recently completed or currently ongoing phase II and III IPF clinical trials in the context of their putative mechanisms of action and the aberrant repair processes they are believed to target: innate immune activation and polarization, fibroblast accumulation and myofibroblast differentiation, or extracellular matrix deposition and stiffening. Placed in this context, the positive results of recently completed trials of pirfenidone and nintedanib, and results that will come from ongoing trials of other agents, should provide valuable insights into the still-enigmatic pathogenesis of this disease, in addition to providing benefits to patients with IPF.
Tissue stiffening is a hallmark of fibrotic disorders but has traditionally been regarded as an outcome of fibrosis, not a contributing factor to pathogenesis. In this study, we show that fibrosis ...induced by bleomycin injury in the murine lung locally increases median tissue stiffness sixfold relative to normal lung parenchyma. Across this pathophysiological stiffness range, cultured lung fibroblasts transition from a surprisingly quiescent state to progressive increases in proliferation and matrix synthesis, accompanied by coordinated decreases in matrix proteolytic gene expression. Increasing matrix stiffness strongly suppresses fibroblast expression of COX-2 (cyclooxygenase-2) and synthesis of prostaglandin E₂ (PGE₂), an autocrine inhibitor of fibrogenesis. Exogenous PGE₂ or an agonist of the prostanoid EP2 receptor completely counteracts the proliferative and matrix synthetic effects caused by increased stiffness. Together, these results demonstrate a dominant role for normal tissue compliance, acting in part through autocrine PGE₂, in maintaining fibroblast quiescence and reveal a feedback relationship between matrix stiffening, COX-2 suppression, and fibroblast activation that promotes and amplifies progressive fibrosis.
Idiopathic pulmonary fibrosis (IPF) is the most common of the idiopathic interstitial pneumonias and is characterised by progressive accumulation of scar tissue in the lungs. The objective of this ...study was to describe the current mortality rates due to IPF in Europe, based on the World Health Organization (WHO) mortality database.We used country-level data for IPF mortality, identified in the WHO mortality database using International Classification of Diseases 10th Edition (ICD-10) codes, for the period 2001-2013. Joinpoint analysis was performed to describe trends throughout the observation period.The median mortality was 3.75 per 100 000 (interquartile range (IQR) 1.37-5.30) and 1.50 per 100 000 (IQR 0.65-2.02) for males and females, respectively. IPF mortality increased in the majority of the European Union (EU) countries with the exceptions of Denmark, Croatia, Austria and Romania. There was a significant disparity in rates across Europe, in the range 0.41-12.1 per 100 000 for men and 0.24-5.63 per 100 000 for women. The most notable increases were observed in the United Kingdom and Finland. Rates were also substantially higher in males, with sex disparity increasing across the period.The reported IPF mortality appears to be increasing across the EU; however, there is substantial variation in mortality trends and overall reported mortality rates between countries.
Vascular permeability in the fibrotic lung Probst, Clemens K; Montesi, Sydney B; Medoff, Benjamin D ...
European respiratory journal/The European respiratory journal,
07/2020, Letnik:
56, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Idiopathic pulmonary fibrosis (IPF) is thought to result from aberrant tissue repair processes in response to chronic or repetitive lung injury. The origin and nature of the injury, as well as its ...cellular and molecular targets, are likely heterogeneous, which complicates accurate pre-clinical modelling of the disease and makes therapeutic targeting a challenge. Efforts are underway to identify central pathways in fibrogenesis which may allow targeting of aberrant repair processes regardless of the initial injury stimulus. Dysregulated endothelial permeability and vascular leak have long been studied for their role in acute lung injury and repair. Evidence that these processes are of importance to the pathogenesis of fibrotic lung disease is growing. Endothelial permeability is increased in non-fibrosing lung diseases, but it resolves in a self-limited fashion in conditions such as bacterial pneumonia and acute respiratory distress syndrome. In progressive fibrosing diseases such as IPF, permeability appears to persist, however, and may also predict mortality. In this hypothesis-generating review, we summarise available data on the role of endothelial permeability in IPF and focus on the deleterious consequences of sustained endothelial hyperpermeability in response to and during pulmonary inflammation and fibrosis. We propose that persistent permeability and vascular leak in the lung have the potential to establish and amplify the pro-fibrotic environment. Therapeutic interventions aimed at recognising and "plugging" the leak may therefore be of significant benefit for preventing the transition from lung injury to fibrosis and should be areas for future research.
Aberrant wound-healing responses to injury have been implicated in the development of pulmonary fibrosis, but the mediators directing these pathologic responses have yet to be fully identified. We ...show that lysophosphatidic acid levels increase in bronchoalveolar lavage fluid following lung injury in the bleomycin model of pulmonary fibrosis, and that mice lacking one of its receptors, LPA1, are markedly protected from fibrosis and mortality in this model. The absence of LPA1 led to reduced fibroblast recruitment and vascular leak, two responses that may be excessive when injury leads to fibrosis rather than to repair, whereas leukocyte recruitment was preserved during the first week after injury. In persons with idiopathic pulmonary fibrosis, lysophosphatidic acid levels in bronchoalveolar lavage fluid were also increased, and inhibition of LPA1 markedly reduced fibroblast responses to the chemotactic activity of this fluid. LPA1 therefore represents a new therapeutic target for diseases in which aberrant responses to injury contribute to fibrosis, such as idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease which leads to significant morbidity and mortality from respiratory failure. The two drugs currently approved for clinical use ...slow the rate of decline in lung function but have not been shown to halt disease progression or reverse established fibrosis. Thus, new therapeutic targets are needed. Endothelial injury and the resultant vascular permeability are critical components in the response to tissue injury and are present in patients with IPF. However, it remains unclear how vascular permeability affects lung repair and fibrosis following injury. Lipid mediators such as sphingosine-1-phosphate (S1P) are known to regulate multiple homeostatic processes in the lung including vascular permeability. We demonstrate that endothelial cell-(EC) specific deletion of the S1P receptor 1 (S1PR1) in mice (EC-
) results in increased lung vascular permeability at baseline. Following a low-dose intratracheal bleomycin challenge, EC-
mice had increased and persistent vascular permeability compared with wild-type mice, which was strongly correlated with the amount and localization of resulting pulmonary fibrosis. EC-
mice also had increased immune cell infiltration and activation of the coagulation cascade within the lung. However, increased circulating S1P ligand in ApoM-overexpressing mice was insufficient to protect against bleomycin-induced pulmonary fibrosis. Overall, these data demonstrate that endothelial cell S1PR1 controls vascular permeability in the lung, is associated with changes in immune cell infiltration and extravascular coagulation, and modulates the fibrotic response to lung injury.
Sphingosine 1-phosphate (S1P) is a key endogenous regulator of the response to lung injury, maintaining endothelial barrier integrity through interaction with one of its receptors, S1P(1). The ...short-term administration of S1P or S1P(1) receptor agonists enhances endothelial monolayer barrier function in vitro, and attenuates injury-induced vascular leak in the lung and other organ systems in vivo. Although S1P(1) agonists bind to and activate S1P(1), several of these agents also induce receptor internalization and degradation, and may therefore act as functional antagonists of S1P(1) after extended exposure. Here we report on the effects of prolonged exposure to these agents in bleomycin-induced lung injury. We demonstrate that repeated administration of S1P(1) agonists dramatically worsened lung injury after bleomycin challenge, as manifested by increased vascular leak and mortality. Consistent with these results, prolonged exposure to S1P(1) agonists in vitro eliminated the ability of endothelial cell monolayers to respond appropriately to the barrier-protective effects of S1P, indicating a loss of normal S1P-S1P(1) signaling. As bleomycin-induced lung injury progressed, continued exposure to S1P(1) agonists also resulted in increased pulmonary fibrosis. These data indicate that S1P(1) agonists can act as functional antagonists of S1P(1) on endothelial cells in vivo, which should be considered in developing these agents as therapies for vascular leak syndromes. Our findings also support the hypothesis that vascular leak is an important component of the fibrogenic response to lung injury, and suggest that targeting the S1P-S1P(1) pathway may also be an effective therapeutic strategy for fibrotic lung diseases.
Objective
Enhanced adhesive signaling, including activation of focal adhesion kinase (FAK), is a hallmark of fibroblasts from lung fibrosis patients, and FAK has therefore been hypothesized to be a ...key mediator of this disease. This study was undertaken to characterize the contribution of FAK to the development of pulmonary fibrosis both in vivo and in vitro.
Methods
FAK expression and activity were analyzed in lung tissue samples from lung fibrosis patients by immunohistochemistry. Mice orally treated with the FAK inhibitor PF‐562,271, or with small interfering RNA (siRNA)–mediated silencing of FAK were exposed to intratracheally instilled bleomycin to induce lung fibrosis, and lungs were harvested for histologic and biochemical analysis. Using endothelin 1 (ET‐1) as a stimulus, cell adhesion and contraction, as well as profibrotic gene expression, were studied in fibroblasts isolated from wild‐type and FAK‐deficient mouse embryos. ET–1–mediated FAK activation and gene expression were studied in primary mouse lung fibroblasts, as well as in wild‐type and β1 integrin–deficient mouse fibroblasts.
Results
FAK expression and activity were up‐regulated in fibroblast foci and remodeled vessels from lung fibrosis patients. Pharmacologic or siRNA‐mediated targeting of FAK resulted in marked abrogation of bleomycin‐induced lung fibrosis in mice. Loss of FAK impaired the acquisition of a profibrotic phenotype in response to ET‐1. Profibrotic gene expression leading to myofibroblast differentiation required cell adhesion, and was driven by JNK activation through β1 integrin/FAK signaling.
Conclusion
These results implicate FAK as a central mediator of fibrogenesis, and highlight this kinase as a potential therapeutic target in fibrotic diseases.
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