Activating Transcription Factor 3 Confers Protection against Ventilator-induced Lung Injury

Abstract

Rationale: Ventilator-induced lung injury (VILI) significantly contributes to mortality in patients with acute respiratory distress syndrome, the most severe form of acute lung injury. Understanding the molecular basis for response to cyclic stretch (CS) and its derangement during high-volume ventilation is of high priority. Objectives: To identify specific molecular regulators involved in the development of VILI. Methods: We undertook a comparative examination of cis-regulatory sequences involved in the coordinated expression of CS-responsive genes using microarray analysis. Analysis of stretched versus nonstretched cells identified significant enrichment for genes containing putative binding sites for the transcription factor activating transcription factor 3 (ATF3). To determine the role of ATF3 in vivo, we compared the response of ATF3 gene-deficient mice to wild-type mice in an in vivo model of VILI. Measurements and Main Results: ATF3 protein expression and nuclear translocation is increased in the lung after mechanical ventilation in wild-type mice. ATF3-deficient mice have greater sensitivity to mechanical ventilation alone or in conjunction with inhaled endotoxin, as demonstrated by increased cell infiltration and proinflammatory cytokines in the lung and bronchoalveolar lavage, and increased pulmonary edema and indices of tissue injury. The expression of stretch-responsive genes containing putative ATF3 cisregulatory regions was significantly altered in ATF3-deficient mice. Conclusions: ATF3 deficiency confers increased sensitivity to mechanical ventilation alone or in combination with inhaled endotoxin. We propose ATF3 acts to counterbalance CS and high volume-induced inflammation, dampening its ability to cause injury and consequently protecting animals from injurious CS.

Zinc deficiency primes the lung for ventilator-induced injury

“…Taken together, these results support the emerging concept that lung stretch promotes endogenous protection (84) in addition to better-recognized injury responses. The possibility that beneficial responses lie downstream of pathways otherwise associated with lung injury emphasizes the need to design interventions that selectively enhance lung protection in MV.…”

HLA-B27, but Not HLA-B7, Immunodominance to Influenza Is ERAP Dependent

“…To investigate whether any difference exists in the level of inflammatory cytokines produced in ERAP +/+ and ERAP 2/2 Tg mice, we determined the cytokine profile in serum and lung homogenate of naive and flu-infected mice ( Fig. 3C) (18). As expected, the cytokine level of flu-infected animals was higher than that of its naive controls, confirming previous results (21,22).…”

“…Supernatants were The Journal of Immunologyaliquoted and stored at 220˚C before analysis. Lung tissue homogenates were prepared as described (18). Lung tissues were homogenized in PBS-based buffer (20 mM Tris-Cl, pH 7.5; 1% Triton X; 0.05% SDS; 5 mg/ml deoxycholic acid; 50 mM NaCl; and 1 mM PMSF) containing various protease inhibitors (Roche, Germany).…”

Acquisition of Chemoresistance and Other Malignancy-related Features of Colorectal Cancer Cells Are Incremented by Ribosome-inactivating Stress

“…This process results in the expression of genes important for cellular homeostasis as well as for a variety of processes involved in cell survival, proliferation, death, and inflammatory responses (21,24). Among the stress-adapted genes, activation of transcription factor 3 (ATF3) plays an integral role in pathogenesis by external insults such as ischemic, respiratory and renal injury, carcinogens, mitogenic cytokines, or integrated stress, including RIS (25)(26)(27). ATF3 is a member of the mammalian ATF/cAMP responsive element-binding protein family of transcription factors, which has different functions depending on whether it is working as a homodimer or heterodimer with ATF2, c-JUN, JunB, or JunD (28,29).…”