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Mechanisms of alveolar epithelial injury, repair, and fibrosis.

ABSTRACT: The challenge facing many fibrotic lung diseases is that these conditions usually present late, often after several decades of repetitive alveolar epithelial injury, during which functional alveolar units are gradually obliterated and replaced with nonfunctional connective tissue. The resulting fibrosis is often progressive and, in the case of idiopathic pulmonary fibrosis (IPF), invariably leads to respiratory insufficiency and, ultimately, the premature death of affected individuals. Recent years have seen a greater appreciation of the relative importance of chronic inflammation as a driver of fibrotic responses. Current evidence suggests that IPF arises as a result of repetitive epithelial injury and a highly aberrant wound healing response in genetically susceptible and aged individuals. Nonspecific anti-inflammatory agents offer no clinical benefit, but the potential contribution of maladaptive immune responses in determining outcome is gaining increasing recognition. The importance of key differences in the tissue-regenerative potential in young versus aged individuals is also beginning to be more fully appreciated. Moreover, there is considerable overlap in the mechanisms underlying tissue repair and cancer, and patients with IPF are at heightened risk of developing lung cancer. Progressive fibrosis and cancer may therefore represent the extremes of a highly dysregulated tissue injury response. This brief review focuses on some of this evidence and on our current understanding of abnormal tissue repair responses after chronic epithelial injury in the specific context of IPF.

SUBMITTER: Chambers RC

PROVIDER: S-EPMC4430974 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Mechanisms of alveolar epithelial injury, repair, and fibrosis.

Chambers Rachel C RC Mercer Paul F PF

Annals of the American Thoracic Society 20150301

The challenge facing many fibrotic lung diseases is that these conditions usually present late, often after several decades of repetitive alveolar epithelial injury, during which functional alveolar units are gradually obliterated and replaced with nonfunctional connective tissue. The resulting fibrosis is often progressive and, in the case of idiopathic pulmonary fibrosis (IPF), invariably leads to respiratory insufficiency and, ultimately, the premature death of affected individuals. Recent ye ...[more]

PMID: 25830828

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Project description:Pulmonary fibrosis is a disease in which lung tissues become fibrous and thereby causes severe respiratory disturbances. Various stimuli induce infiltration of macrophages to the respiratory tract, secreting inflammatory cytokines, which subsequently leads to the development of pulmonary fibrosis. Aesculetin, a major component of the sancho tree and chicory, is known to biologically have antioxidant and anti-inflammatory effects. Human alveolar epithelial A549 cells were cultured for 24 h in conditioned media of THP-1 monocyte-derived macrophages (mCM) with 1-20 ?M aesculetin. Micromolar aesculetin attenuated the cytotoxicity of mCM containing inflammatory tumor necrosis factor-? (TNF)-? and interleukin (IL)-8 as major cytokines. Aesculetin inhibited alveolar epithelial induction of the mesenchymal markers in mCM-exposed/IL-8-loaded A549 cells (?47-51% inhibition), while epithelial markers were induced in aesculetin-treated cells subject to mCM/IL-8 (?1.5-2.3-fold induction). Aesculetin added to mCM-stimulated A549 cells abrogated the collagen production and alveolar epithelial CXC-chemokine receptor 2 (CXCR2) induction. The production of matrix metalloproteinase (MMP) proteins in mCM-loaded A549 cells was reduced by aesculetin (?52% reduction), in parallel with its increase in tissue inhibitor of metalloproteinases (TIMP) proteins (?1.8-fold increase). In addition, aesculetin enhanced epithelial induction of tight junction proteins in mCM-/IL-8-exposed cells (?2.3-2.5-fold induction). The inhalation of polyhexamethylene guanidine (PHMG) in mice accompanied neutrophil predominance in bronchoalveolar lavage fluid (BALF) and macrophage infiltration in alveoli, which was inhibited by orally administrating aesculetin to mice. Treating aesculetin to mice alleviated PHMG-induced IL-8-mediated subepithelial fibrosis and airway barrier disruption. Taken together, aesculetin may antagonize pulmonary fibrosis and alveolar epithelial barrier disruption stimulated by the infiltration of monocyte-derived macrophages, which is typical of PHMG toxicity, involving interaction of IL-8 and CXCR2. Aesculetin maybe a promising agent counteracting macrophage-mediated inflammation-associated pulmonary disorders.

Project description:Idiopathic pulmonary fibrosis (IPF) consists of fibrotic alveolar remodeling and progressive loss of pulmonary function. Genetic and experimental evidence indicates that chronic alveolar injury and failure to properly repair the respiratory epithelium are intrinsic to IPF pathogenesis. Loss of alveolar type 2 (AT2) stem cells or mutations that either impair their self-renewal and/or impair their differentiation into AT1 cells can serve as a trigger of pulmonary fibrosis. Recent reports indicate increased YAP activity in respiratory epithelial cells in IPF lungs. Individual IPF epithelial cells with aberrant YAP activation in bronchiolized regions frequently co-express AT1, AT2, conducting airway selective markers and even mesenchymal or EMT markers, demonstrating 'indeterminate' states of differentiation and suggesting that aberrant YAP signaling might promote pulmonary fibrosis. Yet, Yap and Taz have recently also been shown to be important for AT1 cell maintenance and alveolar epithelial regeneration after Streptococcus pneumoniae-induced injury. To investigate how epithelial Yap/Taz might promote pulmonary fibrosis or drive alveolar epithelial regeneration, we inactivated the Hippo pathway in AT2 stem cells resulting in increased nuclear Yap/Taz, and found that this promotes their alveolar regenerative capacity and reduces pulmonary fibrosis following bleomycin injury by pushing them along the AT1 cell lineage. Vice versa, inactivation of both Yap1 and Wwtr1 (encoding Taz) or Wwtr1 alone in AT2 cell stem cells impaired alveolar epithelial regeneration and resulted in increased pulmonary fibrosis upon bleomycin injury. Interestingly, the inactivation of only Yap1 in AT2 stem cells promoted alveolar epithelial regeneration and reduced pulmonary fibrosis. Together, these data suggest that epithelial Yap promotes, and epithelial Taz reduces pulmonary fibrosis suggesting that targeting Yap but not Taz-mediated transcription might help promote AT1 cell regeneration and treat pulmonary fibrosis.

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Mechanisms of alveolar epithelial injury, repair, and fibrosis.

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Mechanisms of alveolar epithelial injury, repair, and fibrosis.

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