Acute Inflammation Induces Insulin-like Growth Factor-1 to Mediate Bcl-2 and Muc5ac Expression in Airway Epithelial Cells

Abstract

Generally, exposure to LPS in human airways occurs in the form of aerosols and causes an acute inflammatory response or exacerbates existing chronic inflammatory conditions by enhancing airway remodeling and associated pathologies. The present study evaluated which inflammatory mediators may be responsible for the expression of Bcl-2 and mucus cell metaplasia when mice are exposed to aerosolized LPS. At 3 days after exposure, aerosolized LPS (for 20-40 min) with the estimated lung deposited dosage of 0, 0.02, 0.2, 1.4, and 20.2 μg showed a characteristic dose-dependent increase in polymorphonuclear neutrophils. Significant increases of proinflammatory mediators, including IL-1β, TNF-α, IL-6, growth-related oncogene or keratinocyte-derived cytokine, IFN-γ-induced protein-10, monocyte chemotactic protein-1, and macrophage inflammatory protein-1α, were detected at the highest doses. In addition to increased numbers of airway epithelial cells, mucus cell numbers and mucus production were increased in a dose-dependent manner. Hyperplastic epithelial cells expressed insulin-like growth factor (IGF)-1 and, similar to previous studies, increased expression of the prosurvival protein Bcl-2 and induced expression of Muc5ac. Suppression of IGF-1 expression using retroviral shRNA blocked Bcl-2 expression in human and murine airway epithelial cells and Muc5ac in primary murine airway epithelial cells. These findings show that acute inflammation induces IGF-1 to mediate Bcl-2 and Muc5ac expression in airway epithelial cells.

Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence

“…Various cell types expressing IGF-1 are found within the lung, including alveolar macrophages, bronchial epithelial cells, and fibroblasts, hence participation of IGF-I in lung disease pathogenesis has been widely reported (40,41). However, circulating IGF-I levels and pathogenic involvement are still unknown in the context of COPD (42).…”

Involvement of Igf1r in Bronchiolar Epithelial Regeneration: Role during Repair Kinetics after Selective Club Cell Ablation

“…Actually, adult mouse lungs displayed the highest level of Igf1r activation of any organ in the mouse upon challenge with Igf1 [52]. This local auto/paracrine action of Igf1/Igf1rcould be relevant not only in airway epithelial cellregeneration, but also foralveolar macrophagefunction, a cell type that also expresshigh levels of both proteins[53, 54]. Furthermore, Igf1r expression in smooth muscle and endothelial cells of pulmonary blood vessels also indicates a role of this receptor in lung vasculature, as described elsewhere [55, 56].…”

Molecular Processes that Drive Cigarette Smoke–Induced Epithelial Cell Fate of the Lung

“…Both IL-1b and IL-18 are secreted as pro forms, and the activated forms are released by the proteolytic activity of caspase-1 as the component of a multiprotein complex referred to as inflammasome. B cell lymphoma (Bcl)-2 and Bcl-X L , primarily known as cell death regulators, are increased in AECs in response to CS or LPS (44)(45)(46), and modulate inflammatory responses by interacting with inflammasome and inhibiting processing of pro-IL-1b and pro-IL-18 (47). Structure-function studies have shown that a 50-aa flexible loop between the first and second a helices of Bcl-2 and Bcl-X L inhibit oligomerization of nucleotide-binding oligomerization domain-like receptor (NLR) pyrin domain containing 1, a prominent member of NLRs and a central component of inflammasome (48).…”