Raghavendran Lab

The Raghavendran Laboratory, led by Dr. Krishnan Raghavendran, studies the inflammatory biology of lung injury with a focus on direct forms of lung injury, including lung contusion and gastric aspiration, in order to develop therapeutic strategies to prevent these injuries from progressing to acute respiratory distress syndrome (ARDS), ventilator-associated pneumonia and respiratory failure.

Through several collaborations, we also work to better understand the biology underlying ultrasound-induced lung injury, and we conduct single-cell imaging and microfluidic studies of the liquid-air interface within the alveoli of the lung.

Our research team has made several discoveries that are clarifying the processes involved in the inflammatory response to lung injury, leading us to identify potential new treatment strategies.

Lung contusion, or bruising of the lung, often results from traumatic injuries such as car crashes and explosions, and it's one of the main causes of acute respiratory distress syndrome (ARDS) and respiratory failure. Gastric aspiration, too, alone or in the presence of lung contusion, can also lead to ARDS. In ARDS, fluid builds up in the lungs and impedes the exchange of gases that normally takes place during breathing. As a result, oxygen levels in the body's cells, blood and other organs, can quickly fall to life-threatening levels, a condition known as hypoxia.

Mortality rates from ARDS are high — approximately 30% to 40% — and carry high economic costs as well, accounting for over 3 million hospital days each year in the United States. Even when patients
receive supportive care, namely low tidal volume ventilation and reduced crystalloid resuscitation, their conditions often still deteriorate. That fact drives our lab to investigate the inflammatory profile of lung contusion, so we can better understand why some patients improve while others worsen. Our goal is to improve outcomes for all of them.

Our research investigates the complex inflammatory processes that follow lung contusion in order to identify the genes and signaling proteins responsible. We are focusing our efforts on the role of alveolar epithelial cells (AECs), previously thought to be "innocent bystanders" in lung contusion, as well as the signaling molecule macrophage chemoattractant protein-1 (MCP-1) and the role of hypoxia inducible factor 1-alpha (HIF-1α). We have also developed an understanding of the role of succinate and other cycle intermediates in the progression of inflammatory response in lung injuries. With greater understanding of the mechanisms involved at the molecular level, our aim is to develop a therapeutic model and strategies to prevent progression of direct lung injury to ARDS and respiratory failure.

Our sustained efforts over the past 14 years have led to several contributions:

• Developed a refined small animal bilateral model for lung contusion and for aspiration-induced lung injury and bacterial pneumonia

• Discovered and characterized the regulatory role of type II alveolar epithelial cells (AECs) in acute inflammation
• Clarified the inflammatory aspects of gastric aspiration and lung injury, including the role of individual aspirate components, as well as the role of signaling molecule macrophage chemoattractant protein (MCP) -1 in inflammation. Our work also led to the first definitive review of the clinical aspects of aspiration-induced lung injury.
• Elucidated the role of MCP-1 in lung contusion, with and without gastric aspiration, and the subsequent inflammatory response
• Discovered that hypoxia and regulation by hypoxia-inducible factors are a key aspect of acute inflammation following direct lung injury in an animal model
• Discovered, in collaboration with Research Professor Douglas Miller in U-M's Department of Radiology, that the use of diagnostic ultrasound to image lung injury can itself induce pulmonary capillary hemorrhage that resembles lung contusion.