Grant: Foundation Grant

Bone-Marrow-Derived Mesenchymal Stromal Cells (Msc); Cytokines; Endotoxin; Icam-1; Lung Injury; Lung Mechanics; Mechanical Ventilation; Mechanotransduction; Neutrophil Peptides; Sepsis

<html> <body> <p>In collaboration with international investigators (Laffey et al, In Preparation), we recently completed a month-long survey (62 countries, 454 Intensive Care Units, &gt;10,000 patients with hypoxemic respiratory failure) which demonstrated a mortality of 30-40%, even in patients without acute respiratory distress syndrome (ARDS). Extrapolating these figures globally there are &gt;~3 million severely hypoxemic patients per year receiving ventilatory support with a mortality rate &gt;30%. There is evidence that part of this mortality is due to ventilator-induced lung injury (VILI) &ndash; the major focus of our program. Our <strong>vision is to build a Centre of Excellence in Mechanical Ventilation (MV) with a focus on VILI. Our Goal is to improve the outcomes of severely hypoxemic patients, and all patients who require MV.</strong> <br> </p> <p>We previously discovered a mechanism called &ldquo;biotrauma&rdquo; that provides much of the intellectual underpinning for lung protective MV strategies that have markedly decreased ARDS mortality. Over the next 7 years we will focus on further reducing VILI using the following approaches:<br> <strong>1. Adapting conventional</strong> <strong>MV strategies to minimize VILI.</strong> Novel forms of adjusting MV [minimization of driving pressure (&#x0394;P=Plateau pressure - PEEP) &amp; neurally adjusted ventilatory assist (NAVA)] will be examined in proof-of-concept studies in patients, and if successful, will be taken to randomized clinical trials (RCT).<br> <strong>2. Examine novel MV strategies with <u>no</u> cyclic lung stretch.</strong> VILI is caused by cyclic lung stretch during tidal ventilation. Constant flow ventilation and the barospirator will be tested to completely remove cyclic stretch in animal models of lung injury. If successful, they will be taken to human proof of concept studies, then if positive to RCTs.<br> <strong>3. Examine VILI and lung remodeling.</strong> We will examine the molecular mechanisms by which VILI leads to lung fibrosis; and attenuate the lung fibrosis by using combined ventilatory and non-ventilatory strategies in preclinical animal studies.<br> <strong>4. Establish biomarker-guide MSC therapy</strong> <strong>in biotrauma.</strong> We will identify the biologic signature underlying lung injury by mapping oxidative and fibrotic profiles to test our hypothesis that the efficacy of mesenchymal stromal cell (MSC) therapy is dependent on the lung microenvironment, and use these as biomarkers to guide timing of MSC therapy in ARDS.<br> <strong>5. Modulating VILI associated inflammatory responses</strong>. VILI can increase susceptibility to bacterial infection resulting in intracellular signaling activation &amp; worsening biotrauma. We will test adjuvant therapeutic approaches targeting both extra- and intracellular signaling pathways in animal models of VILI and in human ARDS samples. We will develop pharmacological approaches to attenuate <b>neutrophil</b><strong>-mediated VILI</strong> by blocking human neutrophil peptides (HNP).<br> </p> <p>We will also develop a comprehensive educational, training, and mentorship program that builds on the large critical mass of investigators in the area of MV/lung injury/sepsis and has ethical interactions with academic/industry collaborations.<br> </p> <p>Our track record demonstrates that we have the requisite expertise and leadership to carry out the scientific program. In addition, we have a group of world-class collaborators/experts in basic biology, physiology, pathology, bioinformatics, proteomics, clinical studies, statistics, trial design and knowledge translation to help carry out the research program.</p> </body> </html>