Role of angiostatin in neutrophil biology and acute lung injury

Acute lung injury is marked by profound neutrophil influx along with fluid accumulation that impairs lung function at the cost of high mortality (up to 40%). Neutrophils are activated and their constitutive apoptosis is inhibited during this phase in order to be competent phagocytes over the next few hours. Activated neutrophils release copious amounts of toxic mediators that cause tissue damage leading to impaired barrier function and finally, impaired lung function. Therefore, one of the critical needs is to identify molecules that regulate neutrophil migration and silence activated neutrophils to prevent exuberant tissue damage. Angiostatin is an anti-angiogenic molecule highly expressed in lavage fluid of patients with acute respiratory distress syndrome. Angiostatin has recently been shown to inhibit neutrophil infiltration in mice peritonitis. However, the role of angiostatin in modulating neutrophil physiology and lung inflammation remains unknown. I studied the role of angiostatin, an anti-angiogenic molecule, in neutrophil activation and recruitment in vivo and in vitro. Angiostatin was endocytosed only by activated neutrophils, inhibited neutrophil polarity in fMLP-activated neutrophils probably through integrin αVβ3, and inhibited MAPK signalling in LPS-activated neutrophils. Angiostatin suppressed formation of reactive oxygen species and activated caspase-3 in neutrophils in both pre-and post-LPS treatments. Finally, angiostatin reduced adhesion and emigration of neutrophils in post-capillary venules of TNFα-treated cremaster muscle. The next study was designed to investigate the role of angiostatin in acute lung injury. I used E. coli lipopolysaccharide induced acute lung injury mouse model to test the effects of angiostatin through analyses of bronchoalveolar lavage and lung tissues. In addition, I made novel use of synchrotron diffraction enhanced imaging of mouse lungs to assess lung area and contrast ratios over 9 hours as surrogates for lung inflammation. Subcutaneous treatment with angiostatin reduced neutrophil influx, protein accumulation, lung Gr1+ neutrophils and myeloperoxidase activity, phosphorylated p38 MAPK without affecting the levels of MIP-1α, IL-1β, KC and MCP-1 in lavage and lung homogenates. Diffraction enhanced imaging showed that angiostatin causes a time-dependent improvement in lung area and lung contrast ratios that reflect improvement in lung edema. Overall, the study shows that angiostatin is a novel inhibitor of acute lung injury in mice. Moreover, DEI offers a highly useful technique in evaluating dynamics of lung inflammation and to investigate the therapeutic impact of new drugs on lung inflammation. I conclude that angiostatin is a novel inhibitor of neutrophil migration, activation and acute lung injury

Toll-Like Receptor 10 in Human Lungs

The biggest infectious disease outbreaks have been respiratory diseases, which are a leading cause to death and disability in humans. Though the use of antibiotics has helped greatly, challenges occur due to the evolution of anti-microbial resistance. Fortunately, the body has an innate immune system that is the primary response when an infection invades the lungs. Toll-like receptors are important for this primary response. They recognize pathogens and initiate a cascade of events to activate an inflammatory response. Toll-like receptor 10, also known as TLR10, has a unique anti-inflammatory function. This is different compared to the other TLRs, since they have pro-inflammatory properties. TLR10 is the latest TLR to be discovered, therefore little data can be found on its expression and very little is known about its function

Lung responses to secondary endotoxin challenge in rats exposed to pig barn air

<p>Abstract</p> <p>Background</p> <p>Swine barn air contains endotoxin and many other noxious agents. Single or multiple exposures to pig barn air induces lung inflammation and loss of lung function. However, we do not know the effect of exposure to pig barn air on inflammatory response in the lungs following a secondary infection. Therefore, we tested a hypothesis that single or multiple exposures to barn air will result in exaggerated lung inflammation in response to a secondary insult with <it>Escherichia coli </it>LPS (<it>E. coli </it>LPS).</p> <p>Methods</p> <p>We exposed Sprague-Dawley rats to ambient (N = 12) or swine barn air (N = 24) for one or five days and then half (N = 6/group) of these rats received intravenous <it>E. coli </it>LPS challenge, observed for six hours and then euthanized to collect lung tissues for histology, immunohistochemistry and ELISA to assess lung inflammation.</p> <p>Results</p> <p>Compared to controls, histological signs of lung inflammation were evident in barn exposed rat lungs. Rats exposed to barn air for one or five days and challenged with <it>E. coli </it>LPS showed increased recruitment of granulocytes compared to those exposed only to the barn. Control, one and five day barn exposed rats that were challenged with <it>E. coli </it>LPS showed higher levels of IL-1β in the lungs compared to respective groups not challenged with <it>E. coli </it>LPS. The levels of TNF-α in the lungs did not differ among any of the groups. Control rats without <it>E. coli </it>LPS challenge showed higher levels of TGF-β2 compared to controls challenged with <it>E. coli </it>LPS.</p> <p>Conclusion</p> <p>These results show that lungs of rats exposed to pig barn air retain the ability to respond to <it>E. coli </it>LPS challenge.</p

RGD-tagged helical rosette nanotubes aggravate acute lipopolysaccharide-induced lung inflammation

Rosette nanotubes (RNT) are a novel class of self-assembled biocompatible nanotubes that offer a built-in strategy for engineering structure and function through covalent tagging of synthetic self-assembling modules (G∧C motif). In this report, the G∧C motif was tagged with peptide Arg-Gly-Asp-Ser-Lys (RGDSK-G∧C) and amino acid Lys (K-G∧C) which, upon co-assembly, generate RNTs featuring RGDSK and K on their surface in predefined molar ratios. These hybrid RNTs, referred to as Kx/RGDSKy-RNT, where x and y refer to the molar ratios of K-G∧C and RGDSK–G∧C, were designed to target neutrophil integrins. A mouse model was used to investigate the effects of intravenous Kx/RGDSKy-RNT on acute lipopolysaccharide (LPS)-induced lung inflammation. Healthy male C57BL/6 mice were treated intranasally with Escherichia coli LPS 80 μg and/or intravenously with K90/RGDSK10-RNT. Here we provide the first evidence that intravenous administration of K90/RGDSK10-RNT aggravates the proinflammatory effect of LPS in the mouse. LPS and K90/RGDSK10-RNT treatment groups showed significantly increased infiltration of polymorphonuclear cells in bronchoalveolar lavage fluid at all time points compared with the saline control. The combined effect of LPS and K90/RGDSK10-RNT was more pronounced than LPS alone, as shown by a significant increase in the expression of interleukin-1β, MCP-1, MIP-1, and KC-1 in the bronchoalveolar lavage fluid and myeloperoxidase activity in the lung tissues. We conclude that K90/RGDSK10-RNT promotes acute lung inflammation, and when used along with LPS, leads to exaggerated immune response in the lung

Greener Journal of Agricultural Sciences Ways to Maximize the Water Use Efficiency in Field Crops -A review

Yields of field crops in Indo-Gangetic plains of India have decreased due to the advent of increasing water scarcity in this century. The water is a very limiting input in this region for the crop production; its efficiency is quite low in the range 30-40 per cent, thereby about 60-70 per cent of irrigation water is lost during conveyance and application. Irrigation farming, the greatest water user of all, has been made responsible for inefficient water use. There is also not available new land for agriculture to meet the demand of ever increasing population in terms of food and clothing. On the other hand, irrigation farming more and more has to compete with other interests for dwindling resources in water. Therefore, there is need to increase the yields and water use efficiency in water limited environments. Thus, this review will focus on the various water economization practices, irrigation scheduling based on consumptive pan evaporative, land configuration, selection of crop, varieties, intercropping, moisture conservation practices, use vegetative barriers, use of transpiration suppressants according to the availability of water. In this article is also discussed the ecological aspect of water, depletion of groundwater resources, the concept of water use efficiency, need to improve the water use efficiency, factors to enhancing the water use efficiency which will help to sustain the resources of water and productivity of crops. This review article would be useful to convey the importance to work out the water use efficiency to indentify the efficient management practices, crop varieties/hybrids to get the higher productivity with the availability of water. With good management and adoption of appropriate practices improved agricultural water conservation and subsequent use of that water for more efficient crop production are possible under both dry land and irrigated area

Adhesion Molecules in Lung Inflammation from Repeated Glyphosate Exposures

Glyphosate is an active ingredient in herbicides. Exposure to glyphosate-based herbicides has been associated with respiratory dysfunctions in agricultural workers. The ability of inhaled glyphosate to induce lung inflammation is not well understood. Further, the role of adhesion molecules in glyphosate-induced lung inflammation has not been studied. We evaluated lung inflammatory responses from single and repeated glyphosate exposures. Male C57BL/6 mice were intranasally exposed to glyphosate (1 μg/40 μL) for 1 day or once daily for 5 days or 10 days. Lung tissue and bronchoalveolar lavage (BAL) fluid were collected and analyzed. Repeated exposure to glyphosate for 5 days and 10 days resulted in an increase in neutrophils in BAL fluid and higher eosinophil peroxidase levels in lungs, with leukocyte infiltration further confirmed through lung histology. Repetitive exposure to glyphosate increased IL-33 and Th2 cytokines IL-5 and IL-13. A single glyphosate treatment revealed expression for ICAM-1, VCAM-1, and vWF adhesion molecules in the perivascular region of lung sections; with repeated treatment (5 and 10 days), adhesion molecule expression was found in the perivascular, peribronchiolar, and alveolar regions of the lungs. Repetitive exposure to glyphosate induced cellular inflammation in which adhesion molecules may be important to the lung inflammatory process