Oxidant-induced injury to the lung is associated with extensive damage to the lung epithelium. Instillation of keratinocyte growth factor (KGF) in the lungs of animals protects animals from oxidantinduced injury but the mechanism of protection is not well understood. An inherent problem in studying KGF function in vivo has been that constitutive overexpression of KGF in the lung causes embryonic lethality with extensive pulmonary malformation. Here we report the development of a stringently regulated, tetracyclineinducible, lung-specific transgenic system that allows regulated expression of KGF in the lung without causing developmental abnormalities from leaky KGF expression. By using this system, we show that exposure of KGF-expressing mice to hyperoxia protects the lung epithelium but not the endothelium from cell death in accordance with the selective expression of KGF receptor on epithelial and not on endothelial cells. Investigations of KGFinduced cell survival pathways revealed KGF-induced activation of the multifunctional pro-survival Akt signaling axis both in vitro and in vivo. Inhibition of KGF-induced Akt activation by a dominantnegative mutant of Akt blocked the KGF-mediated protection of epithelial cells exposed to hyperoxia. KGF-induced Akt activation may play an important role in inhibiting lung alveolar cell death thereby preserving the lung architecture and function during oxidative stress.

Diabetes is one of common endocrine and metabolic disorder diseases, and it leads to multiple complications causing uncountable suffering and incalculable economic losses to worldwide patients. 1 Globally, the number of people with diabetes mellitus has quadrupled in the past three decades. About 1 in 11 adults now have diabetes mellitus, and 90% of them are type 2 diabetes. 2 Diabetes has increasingly become a global problem to be solved urgently.

Keloids exhibit metabolic reprogramming including enhanced glycolysis and attenuated oxidative phosphorylation. Hypoxia induces a series of protective responses in mammalian cells. However, the metabolic phenotype of keloid fibroblasts under hypoxic conditions remains to be elucidated. The present study aimed to investigate glycolytic activity, mitochondrial function and morphology, and the HIF1α and PI3K/AKT signaling pathways in keloid fibroblasts (KFB) under hypoxic conditions. Our results showed that hypoxia promoted proliferation, migration invasion and collagen synthesis and inhibited apoptosis in KFB. The mRNA levels, protein expressions and enzyme activities of glycolytic enzymes in KFB were higher than those in normal skin fibroblasts (NFB) under normoxia. Moreover, hypoxia remarkedly upregulated glycolysis in KFB. Decreased activities of mitochondrial complexes and abnormal mitochondria were detected in KFB under normoxic conditions and the damage was aggravated by hypoxia. An intracellular metabolic profile assay suggested hypoxia increased glycolytic parameters except glycolytic reserve but inhibited the key parameters of mitochondrial function apart from H + leak. Protein levels of HIF1α and phosphorylation levels of the PI3K/AKT signaling pathway were upregulated in the context of 3% oxygen. Enhanced total reactive oxygen species (ROS), mitochondrial ROS (mitoROS) and antioxidant activities of KFB were observed in response to hypoxia. Additionally, autophagy was induced by hypoxia. Our data collectively demonstrated potentiated glycolysis and attenuated mitochondrial function under hypoxia, indicating that altered glucose metabolism regulated by hypoxia could be a therapeutic target for keloids.

Abstract-Receptor-associated late transducer (RALT) is a feedback inhibitor of epidermal growth factor receptor signaling. RALT has been shown previously to be induced in the ischemic heart and to promote cardiomyocyte apoptosis in vitro. However, the role of RALT in cardiac hypertrophy remains unclear. We hypothesized that forced expression of RALT in the murine heart would protect the heart against cardiac hypertrophy in vivo. We investigated the effect of cardiac overexpression of rat RALT on cardiac hypertrophy induced by angiotensin II and isoproterenol in RALT transgenic mice and wild-type littermates. The extent of cardiac hypertrophy was assessed by 2D and M-mode echocardiography as well as by molecular and pathological analyses of cardiac samples. Constitutive expression of rat RALT in cardiac myocytes of murine heart attenuated both hypertrophic and inflammatory responses and preserved cardiac function. These beneficial effects were associated with the attenuation of the epidermal growth factor receptor-dependent cascade that was triggered by angiotensin II and isoproterenol stimulation. Additional evidence demonstrated that RALT expression blocked fibrosis in vivo and collagen synthesis in vitro. Therefore, cardiac overexpression of RALT improves cardiac function and inhibits maladaptive hypertrophy, inflammation, and fibrosis through attenuating epidermal growth factor receptor-dependent signaling. Key Words: RALT Ⅲ EGFR Ⅲ ERK1/2 Ⅲ cardiac hypertrophy Ⅲ heart failure Ⅲ fibrosis C ardiac hypertrophy is a response of the myocardium to increased workload, characterized by increased myocardial mass with extracellular matrix accumulation. 1,2 Although initially a beneficial adaptive response, prolonged hypertrophy may result in ventricular dilatation and heart failure. 3,4 One evolving concept is that the underlying signaling mechanism, rather than the presence of hypertrophy alone, may determine the functional outcome of cardiac hypertrophy. Thus, it is important to define and modulate the specific signaling mechanism activated by each hypertrophic stimulus and its effect on the cardiac phenotype.Epidermal growth factor receptor (EGFR) transactivation is an important step in the activation of downstream tyrosine kinases and serves as a scaffold for various signaling molecules in cardiac myocytes. 5 Inhibition of EGFR activation by its inhibitor AG1478 and the metalloproteinase inhibitor BB94 significantly attenuated cardiac hypertrophy in vitro and in vivo. 6,7 However, neither systemic effects of these interventions nor nonspecific effects of the chemical inhibitors can be excluded. Indeed, Kagiyama et al 8 showed that inhibition of EGFR by antisense oligonucleotides in mice caused a significant reduction of blood pressure, which could secondarily affect the extent of cardiac hypertrophy. These observations prompted us to investigate a molecular target that specifically blocks EGFR transactivation for inhibiting cardiac hypertrophy and heart failure. One such protein is receptor-associated late transduc...