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Melior Discovery inflammation/arthritis

LPS-Pulmonary Inflammation

Airway diseases such as chronic pulmonary inflammation (including chronic obstructive pulmonary disease and asthma) exact an ever-increasing toll on human health as the population ages and environmental pollutants (including tobacco smoke) damage lung tissue of young and old alike.  These conditions are induced and exacerbated by pro-inflammatory molecules keyed to respond to acute infection, but often result in chronic immunological responses that induce acute crises and damage lung tissue over time. 

 

An important goal in pharmaceutics is to break the inflammatory cascade by blockage or suppression of specific cytokines and chemokines known to induce and amplify lung inflammation. Two such proteins, monocyte chemoattractant protein (MCP-1), and tumor necrosis factor alpha (TNF-α), are found to be associated with early and chronic infection and inflammation in humans, and are mirrored in rodent models of airway inflammation.

 

Intranasal administration of lipopolysaccharide (LPS), a bacterial endotoxin, has been shown to initiate a pro-inflammatory response in the lungs of mice. This modelrecapitulates aspects of the inflammatory cascades that are associated with inflammatory lung disease in humans, and so is useful as a screen for compounds that may disrupt these cascades and attenuate or abort the disease process.  In this study, we used steroidal anti-inflammatory Dexamethasone to pharmacologically validate this model of MCP-1 induction in mice four afters after LPS pulmonary challenge. 

       LPS induced pulmonary inflammation MCP-1 levels

After acute sensitization via intranasal administration of LPS, mice were positioned to provide optimal inhalation and passive gravitational flow of LPS directly to the lungs for approximately five minutes to allow the fullest penetration of LPS to the lungs before awakening.  Four hours after LPS challenge, lungs were dissected, collected and processed for MCP-1 ELISA analyses. Dissected lungs from vehicle and Dexamethasone groups resulted in similar weights (A); however, Dexamethasone administration significantly suppressed levels of MCP-1 in the lungs compared to vehicle treated mice (B).  Data are mean ± SEM; ***p<0.001 compared to vehicle. 

 

Dexamethasone was able to signficantly reduce the levels of MCP-1 in lung tissue four hours after LPS challenge.  This model stands as a good predictor of pulmonary anti-inflammatory compounds.  As a screen, it can point the way for further studies of promising compounds, in viewing relative levels of cytokine MCP-1. 

 

If you are interested in learning more about LPS - Pulmonary Inflammation, please contact models@meliordiscovery.com to start the conversation.