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.

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.

These results demonstrate the application of functional genomics to the molecular "fingerprinting" of acute lung injury and the potential for decoupling biophysical from biochemical injury.

High-volume ventilation induces pentraxin 3 expression in multiple acute lung injury models in rats. Am J Physiol Lung Cell Mol Physiol 292: L144 -L153, 2007. First published August 25, 2006; doi:10.1152/ajplung.00002.2006 is an acutephase protein, which can be produced by a variety of tissue cells at the site of infection or inflammation. It plays an important role in innate immunity in the lung and in mediating acute lung injury. The aim of this study was to determine the effect of mechanical ventilation on PTX3 expression in multiple lung injury models. Male SpragueDawley rats were challenged with intravenous injection of lipopolysaccharide (LPS) or hemorrhage followed by resuscitation (HS). The animals were then subjected to either relatively higher (12 ml/kg) or lower (6 ml/kg, positive end-expiratory pressure of 5 cmH 2O) volume ventilation for 4 h. High-volume ventilation significantly enhanced PTX3 expression in the lung, either alone or in combination with LPS or hemorrhage. A significant increase of PTX3 immunohistochemistry staining in the lung was seen in all injury groups. The PTX3 expression was highly correlated with the severity of lung injury determined by blood gas, lung elastance, and wet-to-dry ratio. To determine the effects of HS, LPS, or injurious ventilation (25 ml/kg) alone on PTX3 expression, another group of rats was studied. Injurious ventilation significantly damaged the lung and increased PTX3 expression. A local expression of PTX3 induced by high-volume ventilation, either alone or in combination with other pathological conditions, suggests that it may be an important mediator in ventilator-induced lung injury.pentraxin; inflammation; ventilator-induced lung injury; sepsis; hemorrhagic shock

The optimal time for post-mortem heparinization in lung transplantation from non-heart-beating donors is approximately 30 minutes after cardiac arrest.

Postmortem heparinization by cardiac massage is beneficial in lung transplantation from non-heart beating donors by preventing microthrombus formation.

Pentraxin 3 (PTX3) is suggested to play important roles in the innate resistance against pathogens, regulation of inflammatory reactions, and clearance of apoptotic cells. PTX3 is the first long pentraxin identified. Long pentraxin shares a C-terminal pentraxin domain with the classical short pentraxin (C-reactive protein, serum amyloid P), but holds an unrelated N-terminal domain that is unique to the long pentraxin. While the short pentraxin is produced only in the liver, PTX3 is made by diverse types of cells, prominently endothelial cells and macrophage, in response to inflammatory signals. Unlike the short pentraxin, the expression of PTX3 in multiple types of tissue cells implies a mechanism for local amplification of innate resistance at the site of infection and inflammation. PTX3 plasma levels are very low in normal subjects but are rapidly increased by inflammatory conditions resulting from a wide range of diseased states, from infection to autoimmune and degenerative disorders. Critically ill patients show elevated circulating levels of PTX3 which are determined by the severity of the disease. Clinical evidence has demonstrated that the elevated PTX3 levels might be a useful early and sensitive marker for severely ill patients. Further studies will definitely be needed to deepen our understanding of PTX3.

Acute inflammatory responses are one of the major underlying mechanisms for tissue damage of multiple diseases, such as sepsis and acute lung injury. Inflammatory mediators released from a variety of cells in response to acute inflammations can interact with immune cells, microvascular endothelial cells and other tissue cells, to elicit a series of intracellular signaling reactions where activation of Src protein tyrosine kinase (PTK) family members is involved. Using cellular and molecular approaches and transgenic animals, Src PTK family members have been identified to be essential for the recruitment and activation of monocytes, macrophages, neutrophils and other immune cells. Src PTK family members 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 attenuated acute lung injury. Further investigation may lead to the clinical application of these inhibitors as drugs for acute lung injury.