Involvement of c-Jun N-Terminal Kinase in TNF-α–Driven Remodeling

Abstract

Lung tissue remodeling in chronic obstructive pulmonary disease (COPD) is characterized by airway wall thickening and/or emphysema. Although the bronchial and alveolar compartments are functionally independent entities, we recently showed comparable alterations in matrix composition comprised of decreased elastin content and increased collagen and hyaluronan contents of alveolar and small airway walls. Out of several animal models tested, surfactant protein C (SPC)-TNF-a mice showed remodeling in alveolar and airway walls similar to what we observed in patients with COPD. Epithelial cells are able to undergo a phenotypic shift, gaining mesenchymal properties, a process in which c-Jun N-terminal kinase (JNK) signaling is involved. Therefore, we hypothesized that TNF-a induces JNK-dependent epithelial plasticity, which contributes to lung matrix remodeling. To this end, the ability of TNF-a to induce a phenotypic shift was assessed in A549, BEAS2B, and primary bronchial epithelial cells, and phenotypic markers were studied in SPC-TNF-a mice. Phenotypic markers of mesenchymal cells were elevated both in vitro and in vivo, as shown by the expression of vimentin, plasminogen activator inhibitor-1, collagen, and matrix metalloproteinases. Concurrently, the expression of the epithelial markers, E-cadherin and keratin 7 and 18, was attenuated. A pharmacological inhibitor of JNK attenuated this phenotypic shift in vitro, demonstrating involvement of JNK signaling in this process. Interestingly, activation of JNK signaling was also clearly present in lungs of SPC-TNF-a mice and patients with COPD. Together, these data show a role for TNF-a in the induction of a phenotypic shift in vitro, resulting in increased collagen production and the expression of elastin-degrading matrix metalloproteinases, and provide evidence for involvement of the TNF-a-JNK axis in extracellular matrix remodeling.

Progress in the mechanism and targeted drug therapy for COPD

“… 72 TNF-α stimulates the pulmonary microvascular endothelial cells to promote the accumulation, adhesion and migration of the polymorphonuclear leucocytes by inducing the expression of IL-8 and upregulating endothelial adhesion molecules, causes release of lysosomal enzymes, elastase and large quantities of ROS; and damages the endothelial cells and alveolar epithelium. 76 TNF-α together with IL-1β has been identified as a key cytokine that is able to initiate inflammatory cascades during exacerbations of COPD. Monocyte chemotactic protein (MCP-1, CCL-2), macrophage inflammatory protein-1α (MIP-1α, CCL-3) are CC-chemokines, which act as chemoattractants for inflammatory cells like macrophages, lymphocytes.…”

<p>How Do Innate Immune Cells Contribute to Airway Remodeling in COPD Progression?</p>

“…Although small in number, M1 macrophages exhibit enhanced pro-inflammatory effects, produce more TNF-α, and enhance ECM deposition in the lung in COPD; and M1 macrophages are responsible for matrix metalloproteinase (MMP) production in COPD, which is related to elastin breakdown and excessive accumulation of collagen or fibronectin in the parenchyma. 50,51 Thus, macrophages in COPD exhibit phenotypic alteration, attenuate phagocytosis, and are involved in airway injury and remodeling.…”

Vitamin C in Stem Cell Biology: Impact on Extracellular Matrix Homeostasis and Epigenetics

“…TGF β can increase collagen synthesis also by inducing the cleavage of the cAMP response element-binding protein 3-like 1 (CREB3L1) transcription factor [ 69 ]. Of note, collagen synthesis may be induced also independently of the TGF β signaling as described during hypoxia-dependent mesenchymalization of human lung epithelial A549 cell line [ 70 ].…”