No abstract

Acute inflammatory responses are one of the major underlying mechanisms for tissue damage of multiple diseases, such as ischemia-reperfusion injury, sepsis, and acute lung injury. By use of cellular and molecular approaches and transgenic animals, Src protein tyrosine kinase (PTK) family members have been identified to be essential for the recruitment and activation of monocytes, macrophages, neutrophils, and other immune cells. Src PTKs also play a critical role in the regulation of vascular permeability and inflammatory responses in tissue cells. Importantly, animal studies have demonstrated that small chemical inhibitors for Src PTKs attenuate tissue injury and improve survival from a variety of pathological conditions related to acute inflammatory responses. Further investigation may lead to the clinical application of these inhibitors as drugs for ischemia-reperfusion injury (such as stroke and myocardial infarction), sepsis, acute lung injury, and multiple organ dysfunction syndrome.

Physical forces play important roles in regulating cell proliferation, differentiation, and death by activating intracellular signal transduction pathways. How cells sense mechanical stimulation, however, is largely unknown. Most studies focus on cellular membrane proteins such as ion channels, integrins, and receptors for growth factors as mechanosensory units. Here we show that mechanical stretch-induced c-Src protein tyrosine kinase activation is mediated through the actin filament-associated protein (AFAP). Distributed along the actin filaments, AFAP can directly active c-Src through binding to its Src homology 3 and/or 2 domains. Mutations at these specific binding sites on AFAP blocked mechanical stretch-induced c-Src activation. Therefore, mechanical force can be transmitted along the cytoskeleton, and interaction between cytoskeletal associated proteins and enzymes related to signal transduction may convert physical forces into biochemical reactions. Cytoskeleton deformation-induced proteinprotein interaction via specific binding sites may represent a novel intracellular mechanism for cells to sense mechanical stimulation.

Long pentraxin 3 (PTX3), an acute-phase protein, is a newly clarified mediator for innate immunity and inflammation. As a soluble pattern recognition receptor, it has a nonredundant role in antifungal infection. Overexpression of PTX3 worsens acute lung injury. The lung epithelium is a critical factor in defense against pulmonary pathogens; it is also involved in acute inflammatory responses related to tissue injury. However, very little is known about how PTX3 is regulated in the lung epithelium. In this study, we found that i.v. injection of LPS induced PTX3 expression in rat lung alveolar epithelium. Using human lung cell lines and primary epithelial cells, we found that PTX3 expression was significantly up-regulated by TNF-α in a time- and dose-dependent manner, but not by LPS. Pretreatment with either actinomycin D or cycloheximide abolished TNF-α-induced PTX3 expression, indicating the requirement for both transcriptional and translational regulation. The TNF-α-induced PTX3 expression was blocked by SP600125, a JNK-specific inhibitor, but not by the inhibitors against NF-κB, ERKs, or p38 MAPK. Knockdown of either JNK1 or JNK2 with small interfering RNA also significantly reduced the regulated PTX3 expression. Thus, lung epithelial cells appear to be a major local source for PTX3 production, which could be induced in vivo from these cells by LPS or other inflammatory stimuli, and may be an important mediator for host defense and tissue damage. The importance of the JNK pathway for the regulated PTX3 expression may be a potential target for its regulation in the lung.