Protease-antiprotease imbalance and oxidative stress are considered to be major pathophysiological hallmarks of severe obstructive lung diseases including chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF), but limited information is available on their direct roles in the regulation of pulmonary phenotypes. Here, we utilized βENaC-transgenic (Tg) mice, the previously established mouse model of severe obstructive lung diseases, to produce lower-mortality but pathophysiologically highly useful mouse model by backcrossing the original line with C57/BL6J mice. C57/BL6J-βENaC-Tg mice showed higher survival rates and key pulmonary abnormalities of COPD/CF, including mucous hypersecretion, inflammatory and emphysematous phenotypes and pulmonary dysfunction. DNA microarray analysis confirmed that protease- and oxidative stress-dependent pathways are activated in the lung tissue of C57/BL6J-βENaC-Tg mice. Treatments of C57/BL6J-βENaC-Tg mice with a serine protease inhibitor ONO-3403, a derivative of camostat methylate (CM), but not CM, and with an anti-oxidant N-acetylcystein significantly improved pulmonary emphysema and dysfunction. Moreover, depletion of a murine endogenous antioxidant vitamin C (VC), by genetic disruption of VC-synthesizing enzyme SMP30 in C57/BL6J-βENaC-Tg mice, exaggerated pulmonary phenotypes. Thus, these assessments clarified that protease-antiprotease imbalance and oxidative stress are critical pathways that exacerbate the pulmonary phenotypes of C57/BL6J-βENaC-Tg mice, consistent with the characteristics of human COPD/CF.

Background: Single immunoglobulin interleukin-1 receptor-related molecule (SIGIRR) is a negative inflammatory regulator whose regulatory mechanism is mainly described in epithelial tissues. Results: Higher monocytic and neutrophilic SIGIRR expression is maintained by Sp1. Conclusion: Lipopolysaccharide decreases SIGIRR expression by suppressing Sp1 via the TLR4-p38 pathway. Significance: The LPS-dependent SIGIRR down-regulation may be critical for optimal inflammatory responses in immune cells.

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Otitis media (OM) is the most common bacterial infection in children, and often leads to conductive hearing loss. The Gram-negative bacterial pathogen, nontypeable Haemophilus influenzae (NTHi) is one of the primary causative agents. A classic hallmark of NTHi-induced OM is inflammation in middle ear. While appropriate inflammation is critical for host defense, an overactive response can often be detrimental to the host. Thus, inflammation must be tightly controlled. Here, we show that NTHi up-regulates the expression of granulocyte macrophage-colony stimulating factor (GM-CSF), one of the major proinflammatory mediator, via MEK-ERK signaling pathway in human middle ear epithelial cells. Moreover, cAMP-dependent protein kinase A (PKA) negatively regulates NTHi-induced GM-CSF expression through inhibition of MEK-ERK signaling pathway. Collectively, our studies unveil a new mechanism underlying the tight regulation of GM-CSF expression via a negative cross-talk between cAMP-PKA and MEK-ERK pathways and may shed light on developing new anti-inflammatory strategies.In the present study, we investigated the role and underlying

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