Acute Lung Injury and COPD

Acute lung injury (ALI), adult respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD) are characterized by neutrophilic inflammation of the lung and marked decreases in lung compliance during ALI or ARDS, however during COPD there is increased lung compliance associated with progressive lung destruction. Although there is no specific treatment for ARDS and ALI, the clinical focus and overall goal is to provide ventilator support while minimizing the deleterious effects of mechanical ventilation on the lung in the form of ventilator induced lung injury (VILI). Due to the chronic nature of COPD, patients are treated with the combination treatment of bronchodilators to ease the work of breathing in conjunction with a corticosteroid to reduce baseline lung inflammation. There are no approved treatments that will reverse the lung destruction that develops during COPD.

LPS-Induced Lung Injury

Biomodels offers a model of lipopolysaccharide (LPS) induced acute lung inflammation.  This paradigm delivers challenges intratracheally or intranasally, and both recapitulate the hallmarks of acute lung injury including neutrophilic influx into the alveolar space, marked increase in lung and systemic inflammatory mediators, pulmonary edema and increased lung elastance (reduced compliance). The length of this model can be tailored to meet a specific application need, but typically lasts between 4-96 hours. Endpoints include broncho-alveolar lavage for total and differential analysis of inflammatory cells as well as cytokine profiling.  Additionally, Biomodels has the capabilities to offer a functional analysis of detailed lung tissue mechanics (forced oscillations, airway hyperreactivity and pressure volume relationships) with the flexiVent mechanical ventilator as well as traditional endpoints such as gas exchange, histopathology and immuno-histochemistry.

Neutrophilic models of inflammation are often used as a model for screening drug candidates or therapies for chronic obstructive pulmonary disease (COPD) and adult respiratory distress syndrome (ARDS).  Glucocorticoids, in the example below dexamethasone, can be used as a positive control for use in LPS models.

Study Design Table

Model Description Duration Endpoints
LPS-Induced Lung Injury Lung injury is induced by intranasal or intratracheal administration of LPS, a TLR-4 agonist 4-96 Hours

Total and differential cell count in the broncho-alveolar lavage (BAL) fluid

Detailed lung mechanics; flexiVent™

BAL inflammatory mediator and total protein content

Histopathology and immunohistochemistry

Gas exchange

Serum markers

Treatment Routes: Intranasal, intratracheal; Microsprayer®, nebulized, intravenous, subcutaneous, intraperitoneal, oral gavage

 

Images from BAL fluid from control (left) and LPS-treated animals (right) demonstrating large increases in neutrophils following LPS-challenge.
Total inflammatory cells and neutrophils recovered in broncho-alveolar lavage fluid 24 hours after intranasal delivery of LPS demonstrate dose response increase in inflammatory cells.
H&E stained lung sections from mice 24 hours after intranasal delivery of LPS.
Total neutrophils and IL-6 recovered in broncho-alveolar lavage fluid as well as lung tissue elastance 24 hours after intranasal delivery of LPS. Light blue bars indicate significantly reduced neutrophilia, IL-6 and IL-1β content and lung elastance in LPS challenged mice that received 3 mg/kg dexamethasone I.P. prior to challenge.
H&E stained lung sections from naïve mice and 24 hours after intranasal delivery of LPS with and without 3 mg/kg dexamethasone.
Pressure volume curves of LPS challenged mice demonstrate increased lung stiffness post challenge that is significantly reduced with dexamethasone treatment.
Hydrochloric Acid-Induced Lung Injury

Biomodels offers a model of hydrochloric acid-induced acute lung inflammation. For this model, the challenge is delivered intratracheally which reproduces the hallmarks of acute lung injury including neutrophilic influx into the alveolar space, marked increase in lung and systemic inflammatory mediators, pulmonary edema and increased lung elastance (reduced compliance). This model generally lasts between 1-96 hours but can be customized to meet a specific application need. Like the LPS model, endpoints include broncho-alveolar lavage for total and differential analysis of inflammatory cells as well as cytokine profiling. Additionally, Biomodels has the capabilities to provide a functional analysis of detailed lung tissue mechanics (forced oscillations, airway hyperreactivity and pressure volume relationships) with the flexiVent mechanical ventilator as well as traditional endpoints such as gas exchange, histopathology and immuno-histochemistry.

Study Design Table

Model Description Duration Endpoints
Hydrochloric Acid-Induced Lung Injury Lung injury is induced by intratracheal administration of 0.1 N HCl 1-96 Hours

Total and differential cell count in the broncho-alveolar lavage (BAL) fluid

Detailed lung mechanics; flexiVent™

BAL inflammatory mediator and total protein content

Histopathology and immunohistochemistry

Gas exchange

Serum markers

Treatment Routes: Intranasal, intratracheal; Microsprayer®, nebulized, intravenous, subcutaneous, intraperitoneal, oral gavage

 

Total neutrophils and total protein recovered in broncho-alveolar lavage fluid as well as lung tissue elastance 24 hours after intranasal delivery of 50, 62.5 or 75 µL 0.1 N HCl. Each indicator increased in a dose responsive manner indicating escalating inflammatory response and increasing lung stiffness(reduced compliance).
Pressure volume curves of HCl challenged mice demonstrate increased lung stiffness post challenge.
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