Metalloproteinases Potential New Biomarkers for IPF, Study Indicates

A class of molecules called matrix metalloproteinases (MMPs) and tissue metalloproteinase inhibitors (TIMPs) show promise as biomarkers of the presence of idiopathic pulmonary fibrosis (IPF), according to a new study.

MMPs and TIMPs are present at elevated levels in the bloodstream of IPF patients, and some of these proteins also might be associated with measures of disease severity, but further studies are needed.

The study, “Circulating matrix metalloproteinases and tissue metalloproteinase inhibitors in patients with idiopathic pulmonary fibrosis in the multicenter IPF-PRO Registry cohort,” was published in the journal BMC Pulmonary Medicine.

Pulmonary fibrosis is a condition marked by scarring (fibrosis) of lung tissues, making breathing difficult. Pulmonary fibrosis is called “idiopathic” when the cause of the condition is unknown.

Diagnosing and managing IPF is a challenge. No clinically available biomarkers are currently available to assist diagnosis, or the prediction of disease progression and treatment response.

The lung scarring seen in IPF involves the overproduction of extracellular matrix (ECM), the network of molecules that bind cells together to make larger tissues. MMPs and TIMPs are vital to maintaining a balanced ECM, and their activity is normally very tightly regulated.

Some MMPs have been found at higher levels in IPF patients, and at least one, called MMP7, has been associated with more severe disease. Little is known, however, regarding the full range of MMPs and TIMPs in the context of IPF, especially concerning their utility as biomarkers.

To shed light on this subject, a team led by researchers from Duke University examined data of 300 patients from the U.S. Idiopathic Pulmonary Fibrosis Prospective Outcomes (IPF-PRO) Registry (NCT01915511), alongside 100 healthy controls of similar age, race, and ethnicity.

Results showed that MMP and TIMP levels were consistently higher in IPF patients versus controls, with the exception of TIMP2.

In particular, high levels of MMPs 7, 8, 12, and 13, as well as TIMP4 were associated significantly with a decreased ability to transfer oxygen into the blood (a measure called DLco) and with higher (meaning worse) CPI scores (a measure of disease severity).

Importantly, these findings were determined not to be influenced by a subject’s history of smoking, meaning that they were influenced more by the subject’s disease status, than by an external factor.

One MMP, MMP9, was associated with higher CPI score, but not with lower DLco.

Because nearly all MMPs and TIMPs analyzed appeared elevated in IPF patients, the researchers next asked whether certain sets of these molecules could best discriminate IPF patients from controls.

They discovered that a set of three molecules — TIMP1, MMP8, and MMP9 — were best at separating patients from controls.

Although the team did not find an MMP/TIMP set that could predict the severity and not just the presence of IPF, their results did support some previous evidence that MMP7 might serve as a marker for IPF severity. The team also found MMPs 12 and 13 were associated with worse outcomes, although few clinical data on them currently exist.

Regarding TIMPs, researchers found that TIMP4 was associated with IPF features (lower DLco and higher CPI), which is interesting as it has been found to also correlate with measures of pulmonary hypertension.

The study benefitted from a high number of subjects, drawn from multiple study centers. Nonetheless, it had certain limitations. According to the team, they cannot tell if the higher MMP/TIMP levels correspond to stable patients or to those experiencing active disease progression; and it remains to be seen whether these results are specific to IPF, or also can be found in other non-IPF fibrosis lung diseases.

Overall, the results obtained “further delineate the potential value of selected MMPs or TIMPs as disease-related biomarkers in patients with IPF,” although “further validation will be necessary,” the team concluded.