Konstantin Birukov, MD, PhD

Can a Drug Used to Protect Against Radiation Damage Also Treat Lung Injury?

Acute lung injury (ALI) and the more severe acute respiratory distress syndrome (ARDS) are types of severe, acute lung dysfunction affecting all or most of both lungs that occurs as a result of illness or injury. ARDS has a death rate of 30-40%. Despite recent progress in treatment of acute lung injury, there is still no successful strategy to reduce lung damage and tissue injury in this condition.

Dr. Birukov studied the compound amifostine, a drug used to control some side effects of chemotherapy and radiation therapy, to see whether it could significantly reduce acute lung injury induced by infectious agents. Amifostine belongs to a group of drugs called cytoprotectants, which protect normal tissue from some of the side effects caused by some treatments for cancer.

His research, supported by an American Lung Association Career Investigator Award, demonstrated a protective effect of amifostine on acute lung injury induced by infectious agents. In addition to immediate beneficial effects on disease processes triggered by bacteria in the lung, he also discovered that preventive treatment with much lower doses of amifostine stimulates the body’s own antioxidant defense mechanisms and increases resistance to ventilator induced lung injury (VILI). He discovered the mechanisms underlying amifostine’s protective effects, which may be used to develop novel clinical therapies for the treatment of ALI and VILI.

“American Lung Association awards granted to me and two other recipients, Patrick Singleton and Anna Birukova, allowed us to enhance and extend our research programs, and our interactions were a key element in organizing the Lung Injury Center with the valuable support of the Pulmonary Section and The University of Chicago Department of Medicine,” he says. “Our Center’s major mission is lung research and training the next generation of young scientists.”

Trever Bivona, MD, PhD

Improving Personalized Treatment for Lung Cancer

“This is a watershed moment in the history of cancer treatment research,” says Trever Bivona, MD, PhD, recipient of this year’s American Lung Association Lung Cancer Discovery Award. A growing number of lung cancer patients are being treated with drugs that target the genetic cause of their lung cancer, known as personalized medicine. Yet while patients may respond quickly, they often become resistant to the treatment.

Dr. Bivona’s research focuses on lung cancers that are associated with a particular mutation in a gene called EGFR. Patients with this type of lung cancer are treated with a drug called erlotinib (Tarceva), which blocks the mutant form of EGFR. While the treatment induces tumor regression, the cancers develop resistance to the drug. Dr. Bivona hopes to better understand how lung cancer becomes resistant to erlotinib.

When he analyzed potential genes that might be causing this resistance, using human lung cancer grown in the laboratory and also in mice, he and his team discovered that the most prominent gene involved was one called AXL. This gene is turned on and allows EGFR-mutant lung cancers to survive in the face of erlotinib treatment. He hopes to discover how AXL is turned on in the setting of erlotinib resistance and how AXL promotes erlotinib resistance in lung cancers.

AXL is a type of enzyme called a kinase. “It turns out this class of enzyme is a very good drug target. Kinases can be targeted with potent drugs, and there are a host of therapies that have emerged in the last few years that target kinases, but none of them are highly specific against AXL,” Dr. Bivona says. “Many drug companies have been working on developing new drugs targeting kinases, including AXL. That means we can move rapidly to test drugs that target AXL and potentially use them for clinical testing. This paves the way for very rapid clinical translation.”

He is collaborating with Dr. Kevan Shokat, a Howard Hughes Medical Institute Investigator and chair of the UCSF Department of Cellular and Molecular Pharmacology at the University of California, San Francisco to develop new drugs that target AXL.

“The American Lung Association grant will accelerate this line of investigation,” Dr. Bivona said. “Without this funding, it would be very difficult to go forward with testing drugs and moving the most promising ones toward the clinic. It’s a real catalyst.”

Ming-Hui Fan, MD

A Novel Protein May Protect Lungs Against Scarring After Injury

When Ming-Hui Fan, MD, took care of pulmonary patients during her residency, she was especially moved by those suffering from idiopathic pulmonary fibrosis (IPF). “These patients really stuck out in my memory, because we had no way of helping them,” she says. “When I decided to specialize in pulmonary medicine, IPF was a major area of interest for me.”

IPF is characterized by progressive lung injury and scarring, leading eventually to death within two to four years of diagnosis on average unless the patient undergoes a lung transplant. Little is known about the cause of the disease, and no effective medical treatments exist to reverse or even to slow down its progress.

While doing her pulmonary and critical care fellowship at the University of Pennsylvania, she worked with cancer researcher Ellen Puré, PhD, whose lab had discovered that tissues of patients with IPF had increased levels of a protein called fibroblast activation protein (FAP). This protein has the ability to break down scar tissue in the lung. It is produced in the developing embryo and production is turned off shortly after birth. It is not produced in normal healthy adult tissues.

Dr. Fan found mice bred to be deficient in FAP have decreased survival and increased lung scarring. Her work demonstrates that FAP lessens the degree of pulmonary fibrosis that develops after lung injury in mice. “We don’t have a clear picture of what FAP acts on,” she says. She hopes to gain a greater understanding of this in her current research, which seeks to take what she has learned from mice into humans. To do this, she is studying lung fibroblasts (cells which produce the collagen of scar tissue) grown from the lungs of IPF patients who received transplants.

ldquo;We have shown that FAP plays a protective role in the lung, minimizing scarring after injury,” Dr. Fan notes. “Now we can consider ways to increase FAP expression, enhance enzymatic activity, and try to find out exactly what FAP is affecting in the tissue in order to boost its effect downstream.”

Her American Lung Association Dalsemer Research Grant has provided her the opportunity of having additional staff support. “I’ve been able to get extra hands to help with the work, which has been enormously helpful,” she says. “I can focus more on the big picture.”

Kevin Hill, MD, MHS

TB Drug Could Aid Smoking Cessation

Kevin Hill, MD, MHS is investigating whether an antibiotic already approved by the U.S. Food and Drug Administration for the treatment of tuberculosis will help people quit smoking. Preliminary evidence suggests that the drug, D-cycloserine (DCS), may be able to help smokers make better use of their counseling sessions by enhancing their ability to learn how to avoid smoking.

There is a great need for more effective treatments for smoking cessation, Dr. Hill says. “Success rates for currently available treatments are, at best, around 35 percent at six months.” he notes. “If we could take the best available treatments, such as nicotine replacement therapy (NRT) and cognitive behavioral therapy (CBT), and magnify their effects, it would have a tremendous impact upon millions of smokers who want to quit. If we could boost success rates by an additional 15 percent, for example, that would mean half of smokers would experience some type of success in quitting smoking, and then we’d have a lot more people willing to get into treatment.”

CBT is a type of talk therapy that is used to treat nicotine dependence, as well as a number of other conditions including panic disorder and general anxiety disorder. In CBT for smoking, patients work with their therapist on how to handle high-risk smoking situations so that gradually they will become desensitized to the feelings of craving that occur whenever they are exposed to smoking cues. DCS enhances this process, called extinction learning, by working on receptors in the brain called NMDA receptors, which are associated with learning. “DCS works on these receptors by dampening the reaction, making you more likely to be able to dissociate a cue, such as seeing a cigarette, with a response of wanting to smoke,” Dr. Hill says.

He is thrilled to have received an American Lung Association grant. “We’ve been trying to secure funding for this research for several years, and now that we have it, we are pushing full speed ahead with the study. If we find this drug is effective in helping people to quit smoking, the translation into practice would be relatively quick, since this is a drug that is already readily available.”

Dr. Hill will also study the effects of DCS on learning and memory, through neuropsychological tests. “If the drug is enhancing the extinction learning process, we can use neuropsychological testing to see why it is working,” he says. “That information may help us determine if particular patients are more responsive than others to this treatment.”

Jean-Francois Jasmin, PhD

Can Membrane Protein Prevent Development of Pulmonary Hypertension?

Pulmonary arterial hypertension (PAH) is a disease of high blood pressure in the arteries of the lungs. PAH is progressive and lifethreatening because the pressure in a patient’s pulmonary arteries rises to dangerously high levels, putting a strain on the heart. None of the current drugs cure or halt the progression of this disease.

Caveolin-1, or Cav-1, is a membrane protein that has recently been shown to be involved in the regulation of pulmonary arterial hypertension. Decreases in Caveolin-1 expression have been reported in patients with severe pulmonary arterial hypertension.

Dr. Jasmin used an American Lung Association Biomedical Research Grant to study whether a Caveolin- 1-mimetic peptide can reverse the development of pulmonary arterial hypertension in an animal model. He treated hypertensive rodents at various stages of the disease with a Cav-1-mimetic peptide to see at which point the treatment might decrease pressure in the arteries and improve survival.

He found that administering Cav-1 not only reduced the development of PAH and the enlarged right heart ventricle that accompanies it, but also improved survival in rats. “The results could have a direct impact on the management of human PAH”, Dr. Jasmin says.

He plans to continue investigating the mechanisms underlying the development of pulmonary hypertension. “This Biomedical Research Grant definitely jump-started my pulmonary hypertension research program and I am thankful to the American Lung Association for this opportunity,” he added.

Pushpa Jayaraman, PhD

Learning How the Immune System Defends Itself Against TB Bacteria

Mycobacterium tuberculosis, which causes pulmonary tuberculosis, is able to establish chronic infection in humans and evade the body’s immune system defenses. Pushpa Jayaraman, PhD, used an American Lung Association Senior Research Training Fellowship to study a novel mechanism to kill M. tuberculosis. Dr. Jayaraman, who is from India, is particularly interested in TB, because she has seen the high toll the disease has taken in her country.

Her research is centered on immune system cells called macrophages that are the first line of defense against airborne pathogens. They engulf M. tuberculosis, bringing it to white blood cells called T cells, which should kill the TB germ. However, M. tuberculosis is able to take refuge in macrophages by diverting some host defense mechanisms. This hijacking of the macrophage defense system interferes with the ability of the immune system to protect people from disease.

She focused on recently discovered molecules called Tim3 on the surface of T cells, and how they regulate the macrophage response to M. tuberculosis. Tim3 expression levels on T cells increase following M. tuberculosis infection. She found that mice infected with TB who were treated with the Tim3 protein experienced a dramatic reduction in the TB bacteria in their lungs. Dr. Jayaraman’s American Lung Association grant allowed her to discover the signaling pathways activated by Tim3 in M. tuberculosis-infected macrophages. She studied a novel way in which Tim3 on T cells can activate M. tuberculosis-infected macrophages by binding to its receptor, Galectin-9 (Gal9) on M. tuberculosis-infected macrophages. Gal9 sends a signal into the macrophage and activates it through the secretion of antimicrobial immune system cells called cytokines, such as IL-1b and TNF, arming the macrophages to efficiently kill M. tuberculosis.

Her research demonstrated a new biological function of Tim3, discovering how it stimulates immunity against microbes. Based on her findings, she concludes that Tim3 and Gal9 represent novel cell targets that could be used to develop new medications to activate macrophages to fight TB.

Dr. Jayaraman’s American Lung Association grant led to further grants to study Tim3 and tuberculosis, from the National Institutes of Health and the Harvard University Center for AIDS Research.

Sun Kim, PhD

Finding Effective Ways to Get Korean Americans to Quit Smoking

Korean male immigrants in the United States have the highest rate of current smoking and the highest rate of cancer deaths caused by smoking among subgroups of the Asian American population. However, this is also one of the groups studied least in regards to smoking and smoking cessation. Many Asian Americans, including Korean Americans, tend not to seek treatment for smoking cessation that is available in public healthcare settings due to language and cultural differences. In addition, Korean Americans have been identified as the group with the highest uninsured rate of all racial and ethnic groups, including Hispanics.

In an effort to prevent lung diseases caused by smoking, Dr. Kim sought to identify psychological, social, cultural, and behavioral factors that may predict Korean Americans’ willingness to quit smoking and to seek cessation treatment. She also wanted to explore their experiences with the treatment, particularly regarding actual and perceived difficulties accessing the treatment. Dr. Kim interviewed 168 Korean males and 94 Korean females who had smoked daily for the previous six months. Those who were interested in quitting received smoking cessation counseling. The study helped Dr. Kim to understand how Korean women differ from Korean men in smoking and quitting behaviors, which warrants the development and implementation of gender-specific smoking cessation interventions. She developed a proposal for a smoking cessation program delivered via webcam, which provides privacy in a community with a strong social taboo against women smokers. Dr. Kim notes that many Asian female smokers refuse to seek help because they fear others will find out they smoke. She hopes to find funding for her new study, which will also include other Asian American femal populations.

Dr. Kim has received a National Institutes of Health/ National Institute on Drug Abuse grant to study tobacco dependence treatment for Asian Americans.

Ian Lewkowich, PhD

Why Do Regulatory T Cells Not Work in People with Allergic Asthma?

A complex immune response is involved in asthma, and much is still not understood about this process. Dr. Lewkowich has focused his research on the role a specific cell, a “regulatory” T cell, or TReg, plays in preventing allergic asthma.

TRegs normally help control immune system responses before they become damaging. Tregs inhibit immune responses by acting on two main targets. By targeting other T cells, Tregs can inhibit existing immune responses, while targeting a second cell type, the dendritic cell, prevents the development of immune responses. Dr. Lewkowich found that mice that are susceptible to the development of an experimental form of asthma have many TRegs, but these TRegs do not function like those in mice without asthma.

Through an American Lung Association Senior Research Training Fellowship, Dr. Lewkowich hoped to find out whether the mice with asthma are not producing some substance needed to turn off the responses that cause asthma; whether the TRegs in asthmatic mice are normal, but other cells simply fail to see them, or a combination of the two.

He studied mice that were susceptible to asthma and those that were resistant to asthma, and found although exposure to allergens increased the production of certain substances by Tregs, there were no differences between the two sets of mice. However, when the ability of Tregs to act on another cell involved in the immune response, dendritic cells, was measured, Tregs (whether they came from asthma-susceptible, or asthma-resistant mice) successfully targeted dendritic cells from resistant mice, but not those from susceptible mice. This demonstrates that the defect lay in the ability of dendritic cells to respond to Tregs, not in the Tregs themselves. Further experimentation has revealed that a particular inhibitory pathway crucial for the ability of Tregs to target dendritic cells appears to be non-functional in the mice susceptible to asthma.

Experiments are currently underway to overcome this defect in asthma-susceptible mice, increasing their resistance to the development of allergic asthma.

Joshua Mezrich, MD

Preventing Environmentally Triggered Asthma Flareups

While it has long been known that certain environmental hazards can affect airway disease such as asthma, the way in which some of these toxins cause harm has been unclear. Joshua Mezrich, MD, is researching polycyclic aromatic hydrocarbons, toxic chemicals released into the environment by fossil fuel combustion. A primary route of human exposure to these chemicals is tobacco smoke. He hopes that his investigation will identify an entirely new target for intervention, both before and after environmental exposures, to prevent worsening of airway disease.

“It’s possible that if people are exposed to toxins over a long period, they could alter the immune system,” says Dr. Mezrich. “We are exposed to many of these toxins through pollutants such as cigarette smoke and diesel fuel, all of which are associated with aggravating asthma.”

He is focusing on the receptor through which these hydrocarbons work, known as Aryl Hydrocarbon Receptor (AHR). He screened many small compounds to see which ones activate AHR strongly, and found a few that were not previously known to do so. One of the compounds was designed as a cancer drug that blocks growth of blood vessels in tumors. Dr. Mezrich found the compound activates AHR and helps regulate the immune response. “Although it did not work well against cancer, clinical tests showed it was tolerated, so it could be tested safely for asthma,” he notes.

“If we can prove one of the mechanisms of airway disease involves activation of AHR by environmental exposures, it would open up new ways of regulating this process,” Dr. Mezrich says. He suggested that an inhaled treatment could be developed to modulate the effects of toxins that cause problems in airway disease.

He also hopes to be able to identify which people are at risk from toxic exposures, by looking at their activation of AHR in response to these exposures. “If you can identify people at risk of developing disease before they do so, you might be able to minimize their exposure, or treat them before they develop the disease,” he says. “We hope this research will be very translatable.”

Seyed Javad Moghaddam, MD

Airway Inflammation’s Role in Lung Cancer

Many studies have found that smokers with chronic obstructive pulmonary disease (COPD) have an increased risk of lung cancer compared with smokers with comparable cigarette exposure but without the disease. COPD causes inflammation in the lung, which persists even after a person stops smoking. These facts suggest a link between chronic airway inflammation and lung cancer, but the precise way in which the link works is unknown. It may be a genetic variation in the immune system’s inflammatory response to inhaled smoke and to microorganisms that gather in the airways of smokers.

Through a Lung Cancer Discovery Award, funded in partnership between the American Lung Association and the LUNGevity Foundation, Dr. Moghaddam used a mouse model to study the mechanism responsible for promotion of lung cancer by airway inflammation. He concentrated on a genetic alteration found in COPD and lung cancer, involving a gene called NF-kB and the protein it produces, interleukin 6 (IL-6). Dr. Moghaddam was able to show that COPD-like airway inflammation promotes lung cancer in a mouse model. He found mice whose NF-kB or IL-6 gene was switched off in the airway had a 70% reduction in the number of tumors induced on the surface of the lung compared with mice whose NF-kB or IL-6 gene was not turned off.

This research could lead to development of antiinflammatory therapy in patients with COPD who are at high risk for lung cancer, and in patients with early stage lung cancer.

Dr. Moghaddam was able to use data from this project to apply for and receive a larger grant on dissecting the role of airway inflammation in lung cancer promotion.

Sean Vincent Murphy, PhD

Developing a Cell Therapy for Cystic Fibrosis

Stem cells in amniotic fluid called fetal stem cells may one day be used to treat babies born with cystic fibrosis (CF). Sean Vincent Murphy, PhD, is using an American Lung Association Senior Research Training Fellowship grant to develop cell therapy that can be used to improve the function of abnormal lung cells in CF patients.

Patients with cystic fibrosis have a defect in a gene that allows for proper regulation of salts and water in various tissues. This alteration causes significant problems in the lungs of people with CF. The normal mucus in the lungs becomes thick and dehydrated, and ultimately blocks the airway passages, resulting in a predisposition towards chronic bacterial infections and lung disease.

Dr. Murphy and colleagues have discovered a small number of stem cells in amniotic fluid and placental tissue, called fetal stem cells, which represent an intermediate stage between embryonic stems cells and adult stem cells. Fetal stem cells give rise to many of the specialized cell types found in the human body. They are easily obtainable, since they are found in leftover birth tissue, and can be grown in large quantities—they typically double in number every 36 hours.

The researchers will first attempt to produce functional lung fluid exchanging cells from fetal stem cells. “We will prepare cells for the stresses they will face when they get into the lungs,” Dr. Murphy says. “We place them on a flexible surface that is stretched in a way that’s similar to how lungs stretch during breathing. We’re ‘working out’ the cells so they’re tough enough to survive in the lung environment.”

They will then try to replace the function of lung cells damaged by experimental radiation with fetal stem cells, to see if they can significantly improve function to the dysfunctional lung. They performed studies in which they gave mice a dose of radiation to damage their lung cells. They found that when they administered fetal stem cells through a tube via the trachea or nose, a significant number of cells were successfully implanted in the lungs.

Dr. Murphy says that if the treatment is eventually found to be safe and effective in humans, the treatment could be given to newborns known to have cystic fibrosis through a tube down the trachea—the same type of tube used to inflate the lungs of newborns who are having difficulty breathing.

ldquo;If we were to use the babies’ own cells, we would use gene therapy on the stem cells to repair the damage and then return them to the patient,” he says. “However, we wouldn’t necessarily need to use the patients’ own cells—we can develop large banks of fetal stem cells to be used when they are needed.”

Lee Quinton, PhD

Targeting the Immune System’s Response to Bacterial Pneumonia

Respiratory infection is a leading cause of lung injury and death in the United States. Due to their small size, potentially harmful agents such as bacteria can circumvent initial airway filtration mechanisms, allowing them to invade lower regions of the lung. The body mounts an inflammatory response to bacterial colonization in order to direct the cells of the immune system toward infected airspaces. While this immune response is essential for the clearance of harmful bacteria, it must be precisely regulated in order to prevent lung injury, which can result from excessive inflammation.

Dr. Quinton studied a protein called signal transducer and activator of transcription-3 (STAT3) which is activated within cells during the immune response to lung infection. He hoped to identify factors in the lung that can activate STAT3 and determine the consequence of STAT3 deficiency during bacterial pneumonia.

With the help of his American Lung Association grant, he found that the presence of STAT3 in specific lung cells is required early during infection for promoting inflammation, and is also necessary for limiting inflammation and preventing lung injury at later times. In addition, he identified a previously unrecognized factor that may be most responsible for initiating STAT3 activity in response to lung infection.

The results of this study helped identify specific aspects of the immune system response during pneumonia that can be targeted for therapeutic intervention.

Roxanna E. Rojas, MD, PhD

Gaining Insight into How TB Germ Hides From Immune System

While one-third of the world’s population is currently infected with TB, only about 10 percent of these people will develop TB disease in their lifetime. The remaining 90 percent have what is called latent or inactive TB, meaning their immune system can successfully fight the infection. The TB infection may remain inactive for a lifetime, although latent TB infection can become active if the person’s immune system becomes weakened (such as with HIV infection).

Roxana E. Rojas, MD, PhD, used an American Lung Association Biomedical Research Grant to investigate how the bacteria that causes TB, Mycobacterium tuberculosis, escapes recognition by the immune system and remains latent. Her goal was to gain information that could be used to design better vaccines.

M. tuberculosis appears to inactivate two types of key immune cells: macrophages and T lymphocytes. The TB bacteria primarily reside in macrophages, immune cells that engulf foreign material. Macrophages are activated by proteins called cytokines, which are secreted by T lymphocytes. Dr. Rojas studied the mechanisms that M. tuberculosis uses to inactivate T lymphocytes. She focused on molecules called glycolipids on the surface of the bacteria that affect T lymphocytes. Glycolipids prevent optimal interaction between T lymphocytes and macrophages, which is very important for the development of an effective immune response. In addition, mycobacterial glycolipids directly inactivate T cells, contributing to immune evasion.

Dr. Rojas made substantial progress toward her longterm goal of identifying and characterizing mycobacterial molecules that have a direct regulatory effect on T cell function. During the course of her research, she refined and expanded her original experiment to study the role of molecules other than the one she originally focused on. “This ALA-funded project and follow up studies stemming from it will have a direct impact in vaccine development,” she says. “These findings will help design improved anti- TB vaccines and therapeutic measures to limit TB damage in the lung.”

Since completing her research funded by the American Lung Association, Dr. Rojas received two grants from the National Institutes of Health.

Christina Stallings, PhD

How Protein Helps TB Bacteria Stand Up to Immune System’s Assaults

Mycobacterium tuberculosis (Mtb), which infects one-third of the world’s population, caused an estimated 1.4 million TB-related deaths in 2010. This health crisis is worsened by the alarming emergence of drug-resistant strains.

During infection, mycobacteria must withstand an arsenal of assaults by the body’s immune system. “Mtb is a pretty amazing pathogen,” says Christina Stallings, PhD. “It can infect people for their entire lives, even if they have a robust immune system that fights it.” That is because Mtb has its own defenses that fight the immune system, she explains.

Using an American Lung Association Biomedical Research Grant, Dr. Stallings is studying how Mtb defends itself. She is focusing on a protein called mycobacterial CarD, which regulates the response of Mtb to assaults by the immune system, and is essential for acute and persistent infection.

Dr. Stallings has found that when a mutant form of Mtb that has less CarD is exposed to immune system assaults, the bacteria is much more sensitive and dies much faster. “That showed us that Mtb absolutely needs CarD to combat these stresses imposed by the immune system,” she says. She then used this strain of Mtb and infected mice with it. She found that the mouse immune system was able to kill the bacteria.

In the second year of her grant, Dr. Stallings is studying the mechanism by which CarD helps Mtb fight the immune system. “If we can figure out how it works, we could target it with new antibiotics and chemicals to compromise its activity,” she says.

The American Lung Association grant has been instrumental in her research, she says. “The grant has allowed us to characterize the protein, produce a mutant version of Mtb and bring it to a mouse model. We will apply for funding for a larger National Institutes of Health grant based on everything we’ve done so far, which we hope will lead to new drug targets for TB.”

Martin Steffen, MD, PhD

Study on Protein and Lung Disease Reveals Surprises

Dr. Steffen’s Biomedical Research Grant from the American Lung Association originally focused on the role of a protein called proteasome in chronic obstructive pulmonary disease (COPD). Proteasome is a key protein complex known to regulate several processes that cause inflammation, and which has previously been implicated in the development of diabetes and heart disease.

He isolated proteasome complexes from people with and without COPD, in order to identify differences between the two groups. He compared the protein and chemical composition of the complexes, and tested their functional activity. He was unable to consistently identify differences in protein composition between the two groups.

Fortunately, during his research, he was able to start a very successful line of inquiry on lung cancer. Dr. Steffen’s research centered on a process called phosphorylation, which can turn a protein “on” or “off.”

He identified a number of proteins whose activation allows them to distinguish between cancer cells and normal cells with almost 97 percent accuracy. He also developed a new way to identify key biological pathways that are active in cancer, but not in normal cells. He says his findings will ultimately lead to the development of drugs aimed at inhibiting these cancer-related pathways.

“Despite the fact that these studies represent a very significant departure from the originally proposed experiments, they are squarely aimed at reducing the burden of lung disease in patients, and illuminate biological mechanisms associated with the disease,” Dr. Steffen says.

He is now focused on developing a test to predict lung tumor sensitivity for the drug erlotinib. He hopes to expand this research to include other cancer drugs.

Based on his American Lung Association-funded research, Dr. Steffen applied for further grants to continue his investigations.

Omar Tliba, DVM, PhD

Investigating Causes of Steroid-Resistant Asthma May Lead to New Treatments

Although most people with asthma respond to treatment with corticosteroids, these drugs don’t work in a substantial number of patients. Despite treatment with high doses of corticosteroids, these patients still have persistent lung inflammation and labored breathing, and are at increased risk of dying from asthma attacks.

Advances in understanding the mechanisms that are involved in the diminished action of corticosteroids will lead to the development of more effective therapy for patients who do not respond to steroids. In his American Lung Association-supported research, Dr. Tliba studied airway smooth muscle, a lung tissue that plays a key role in airway inflammation and bronchial hyper-responsiveness (airway “twitchiness”), two main features of asthma.

He hypothesized that chemical messengers called cytokines, which are released by immune cells in response to asthma triggers such as allergens and viruses, reduce the actions of corticosteroids in airway smooth muscle. Dr. Tliba discovered that a molecule called IRF-1 is involved in this process. His research suggests that increasing levels of IRF-1 may represent a novel therapeutic target for treating steroid-resistant asthma.

He then found that steroid resistance induced by protein chemical messengers called cytokines in airway smooth muscle could be reversed by vitamin D. The findings suggest that vitamin D also may exert some beneficial effects in the treatment of steroid-resistant proteins in patients with difficult-to-treat asthma. His research is likely to bring new insight into the development of novel therapeutic treatment of steroid-resistant asthma.

The American Lung association Biomedical Research Grant helped Dr. Tliba to apply for and receive a grant from the National Institutes of Health to study the mechanisms of inflammation-induced steroid resistance in asthma.

Roger Tsien, Ph.D.

Roger Tsien, Ph.D., is a Nobel Prize winner in chemistry who is using his expertise to bring a new perspective to the study of asthma. Dr. Tsien is the first recipient of the American Lung Association/American Asthma Foundation Senior Investigator Award, given to a non-pulmonologist conducting novel and innovative research on asthma.

Dr. Tsien will be focusing on the work of proteases, which are ubiquitous enzymes involved in many biological processes including the inflammation that underlies asthma. Little is known about precisely when and where different proteases become active in asthma. Dr. Tsien, Professor of Pharmacology and Chemistry & Biochemistry at the University of California, San Diego, will use an imaging technique already developed for cancer and apply it to proteases to better understand how they are involved in asthma.

“We realized this imaging technique had many potential applications to other diseases, including atherosclerosis, or hardening of the arteries, which involves immune cells that are attacking blood vessels,” Dr. Tsien says. “It will also apply to asthma, a disease in which immune cells attack lung cells.” The development of agents to target these enzymes for the treatment of asthma requires knowledge of exactly where, when and how they act in the lung. Dr. Tsien’s research, which will be conducted in an animal model, aims to answer these questions. Eventually, Dr. Tsien says the findings from the study could be applied to human patients for diagnosis and potentially for the evaluation of new treatments for asthma.

Dr. Tsien is eager to be studying asthma, which he has had since childhood on the East Coast. “I suffered from allergic asthma as a child,” he says. “Since growing up and moving to California I don’t suffer from allergy-induced asthma anymore, but I can still get exercise-induced asthma, and I carry an inhaler with me at all times. I am hopeful we can make a scientific discovery that could help develop a better understanding of a disease I have experienced personally.” Dr. Tsien was a co-recipient of the 2008 Nobel Prize in chemistry, with Osamu Shimomura and Martin Chalfie, for the discovery and development of the green fluorescent protein, GFP. First observed in jellyfish, GFP has been used to develop ways to watch processes that were previously invisible, such as the development of nerve cells in the brain or how cancer cells spread. “That work, like my asthma research, was also related to imaging biological processes,” he says. The American Lung Association/American Asthma Foundation Senior Investigator Award is a three-year award valued at $250,000 per year.

Click here to read Dr. Tsien's autobiography.

Jae-Kwang Yoo, PhD

How Immune Cells Come to the Rescue Against Influenza

Influenza viruses cause considerable illness and death. Each year, 5% to 20% of the population in the United States contracts influenza. Approximately 200,000 people are hospitalized and as many as 36,000 die from complications associated with seasonal flu. Jae-Kwang Yoo, Ph.D., is trying to gain a better understanding of how the body’s immune system fights the influenza virus. “We can use this information to improve the efficiencies of the vaccine for the seasonal flu, and potentially for a pandemic flu,” he says.

When a person is infected with the influenza virus, the immune system responds using B cells. These cells produce neutralizing antibodies that are essential both to prevent reinfection and to eliminate the infection from the respiratory tract. Once they are activated, B cells proliferate and differentiate, or become specialized. B cells are dependent on immune cells called CD4+ T cells to help with this process. A type of CD4+ T cells called T follicular helper cells (TFH) provide B cells with assistance in fighting influenza, but how these helper cells are generated against influenza is not well understood.

During his PhD training in the lab of Dr. Eleanor N. Fish at the University of Toronto, Dr. Yoo and colleagues identified a new cell involved in fighting against viruses called late activator antigen presenting cell (LAPC). This cell regulates the body’s antibody response, especially in influenza virus infection. Now at the University of Virginia, working with Dr. Thomas J. Braciale, Dr. Yoo has found that LAPCs are potent inducers of TFH response in influenza virus infection. However, the exact way in which the immune system controls this process is still not clear. This is what he aims to understand.

“With the prestigious support from the American Lung Association Research Award, we can be one step closer to be able to provide insights into how our immune system controls antibody response in pulmonary viral infection,” Dr. Yoo says. “Hopefully, my American Lung Association-funded research may provide a framework for the identification of novel targets for therapeutic vaccine development to prevent influenza A virus infection. This will ultimately help save lives.”

Igor Zelko, PhD

Blocking Remodeling in Lung’s Blood Vessels in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a devastating disease; only about half of patients survive five years after diagnosis. The lung’s blood vessels are remodeled and constrict, leading to heart failure due to an enlarged and ineffective right side of the heart. Current drugs used to treat the disease enlarge the blood vessels, but do not block the eventual thickening of the artery walls and do not improve survival. More effective therapies are urgently needed.

With the assistance of an American Lung Association Biomedical Research Grant, Igor Zelko, PhD, is studying the mechanisms that regulate remodeling of blood vessel walls in the lung. He is focusing on a substance that inhibits an enzyme called histone deacetylase, which he hopes will provide clues that could lead to better therapy for PAH.

A process called acetylation, or modification of histones regulates the expression of a major antioxidant enzyme in the pulmonary arteries. Dr. Zelko is investigating whether histone deacetylase inhibitors will significantly elevate levels of this antioxidant enzyme, called extracellular superoxide dismutase, which in turn will reduce or completely block remodeling of the lung’s blood vessel walls and slow or prevent the development of PAH in a mouse model.

“If it is successful, eventually this drug could be used in human trials to stop, or even reverse progression of the disease,” Dr. Zelko says.

He is particularly grateful to the American Lung Association for funding his research. “My startup funding had ended, and if I had not received the American Lung Association grant, I could not have continued this research, which I have been working on for the last 10 years,” he said.