Idiopathic Pulmonary Fibrosis

A mystery wrapped in an enigma—if any lung disorder fits that description, the riddle of idiopathic pulmonary fibrosis (IPF) would be a good candidate.

What makes healthy lung cells that have served a body well for 50 years suddenly lose their ability to repair themselves? Why do alveolar epithelial cells responsible for drawing in the oxygen necessary to sustain life start turning into scar tissue?

The pathogenesis of this progressive lung disease is poorly understood, but Birmingham researchers are uncovering clues that are at least beginning to reveal the shape of some of the puzzle pieces.

“Getting a better understanding of IPF may point us toward viable treatment strategies,” said Victor J. Thannickal, MD, director of the Division of Pulmonary, Allergy and Critical Care Medicine for the School of Medicine at UAB. “There hasn’t been much we could offer IPF patients beyond lung transplants, but we’re hoping that what we learn will lead us to therapies to help halt progression and preserve lung function.”

Thannickal’s research has contributed insights into the role of the NOX4 enzyme in IPF, as well as an intriguing paradox in how lung cells in these patients react to injury. In some patients, myofibroblasts seem to resist the apoptosis process that normally removes these cells, leading to a continuing buildup of scar tissue. At the same time, alveolar epithelial cells seem more susceptible to being taken away before their time. This failure of repair and regeneration results in progressive lung damage.

Other researchers at UAB and Tulane have identified what appears to be an epigenetic suppression of Thy-1, a glycoprotein, in fibroblast development. While most healthy lung tissue is Thy-1 positive, IPF fibroblasts do not express Thy-1, although DNA for the gene seems to be intact. Aberrations in the promoter regions seem to be interfering with expression of the gene.

Another factor UAB researchers have identified that appears to have a role in uncontrolled extracellular matrix production in response to tissue injury is miR-21, which mediates fibrogenic activation of pulmonary fibroblasts.

“The NIH has been extremely supportive of our research efforts,” Thannickal said. “We have several trials underway looking at possible ways to slow down or stop the progression of IPF. Although it hasn’t been considered a common disease in the past, we suspect it is underdiagnosed. With the aging of the population, we expect to see more cases in the future.”

The principal investigator for some of those clinical trials is Joao A. de Andrade, MD, Associate Professor of Medicine at UAB.

“We have seven active studies and one pending approval, and we’re looking at the effectiveness of some older drugs that may be helpful against IPF,” de Andrade said. 

“In two of those trials, we’re following up on clues from studies in Europe and Japan. We’re testing antioxidants in our PANTHER study to see if they can slow the decline of lung function. Our ACE trial is using anticoagulants. There is an ongoing battle between coagulants and anticoagulants, with the balance disrupted in IPF in favor of coagulation. There also seems to be cross talk between coagulation and inflammation. We’re hoping anticoagulants will have an effect on that process.”                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    

Seen mostly in people over 50, IPF is more common in men than women, and occurs more often in Caucasians than other populations. There are familial links in some cases, but many questions are still to be answered in understanding what triggers IPF. Evidence at this time points to an insult to lung tissue in susceptible individuals setting the disease process in motion.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    

“We think the actual occurrence of IPF is significantly underestimated,” de Andrade said. “The presenting symptoms—shortness of breath or a persistent cough, for example—are much like other more common conditions such as COPD or heart disease. However, the possibility of IPF should also be considered.

“Diagnosing this condition as early as possible can make all the difference in getting patients on the lung transplant list while they are still well enough to qualify. Without a transplant, half of IPF patients will die within three years of diagnosis.

“Early diagnosis also helps us get them into the best condition possible before surgery. In managing the condition and minimizing dyspnea, we recommend that IPF patients stay as active as possible, walking more and getting into a pulmonary rehab program.”

The Lung Center at UAB sees IPF patients from across Alabama and as far away as Florida, Georgia and Mississippi. If you have a patient you believe might qualify for one of the ongoing IPF clinical trials at UAB, you can contact the nurse coordinator at 205 934-7630.