Neutrophil illustration. Credit: Getty Images

In alpha-1 antitrypsin deficiency (AATD), one of the most notable clinical manifestations is pulmonary disease, especially emphysema. In fact, studies have shown that AATD is the most common cause of emphysema (aside from cigarette smoking). Other patients with AATD may be diagnosed with bronchiectasis or COPD. Usually, a mixed picture of emphysema, bronchiectasis, and COPD is observed. 

Fazleen and Wilkinson, in their study on the role of proteases in AATD, believe that because the genetic factors that determine AATD phenotype (such as emphysema, COPD, bronchiectasis, a combination of the 3 with varying severity, or no pulmonary disease at all) are so varied, “it is becoming increasingly clear that AATD is not a single entity and that there are distinct phenotypes of disease, albeit with some overlap.”

“Factors that determine what phenotype will be predominant in a particular patient are not currently understood, and research into chronic lung disease phenotypes such as COPD and bronchiectasis has historically excluded patients with AATD,” they wrote. 


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Read more about AATD etiology 

This is an issue that the medical research community needs to address with urgency, as there is still no curative therapy for AATD. AAT augmentation therapy is available and is seen as a viable treatment option. However, Fazleen and Wilkinson noted it is associated with periodic peaks and troughs in drug concentrations, meaning it may not confer consistent lung protection. 

“Augmentation therapy therefore may not be the ultimate solution for patients with AATD, and the disease pathology therefore requires deeper exploration,” they wrote. The route that they have chosen to explore is the role of specific proteases involved in AATD pathophysiology, and whether a deeper understanding of them can result in better treatment strategies.

Neutrophil Activity 

“AATD-related lung pathology is thought to be driven mainly by neutrophils, which navigate via chemotaxis towards sources of inflammation,” Fazleen and Wilkinson explained.

Elizabeth Sapey, MD, wrote in her study on neutrophil modulation in AATD that “studies which have sampled the lungs of patients with AATD describe significant inflammation, and sputum from patients with AATD is highly chemotactic, with increased levels of the neutrophil chemoattractants CXCL8 and LTB4 and high neutrophil counts suggesting these cells are responding to . . . these chemoattractants by passing from blood into the airways.”

The influx of neutrophils into the lungs kicks off a series of events that further lung pathology. According to Fazleen and Wilkinson, “Neutrophils exert their protease-driven effects on the lungs via . . . azurophilic granules, which consist of the main neutrophil serine proteases (NSPs): neutrophil elastase (NE), proteinase-3 (PR3) and cathepsin G (CG).” AAT in healthy individuals protects the lungs by antagonizing excessive NSP activation; in patients with AATD, this function is diminished or lost. 

In summary, neutrophils drive protease activity; because this is uninhibited due to low levels of AAT in AATD, protease activity continues unhindered and proceeds to damage the lung tissues.

Let’s take a closer look at NSPs. NSPs are activated for the purpose of fighting infection, including tissue remodeling and wound healing. However, like the general inflammatory processes in the body, unchecked activity can result in harm instead. In the case of NSPs, excessive activation causes the degradation of the extracellular matrix—one of the main mechanisms of lung damage in AATD patients. 

On this same subject, Sapey wrote, “Once at the site of inflammation, neutrophils are avid and unrestricted phagocytes, engulfing tissue debris, pathogens and damaged cells, but also recruit other neutrophils to the source of inflammation while phagocytosis is still required.” The result is that the swarming of neutrophils causes tissue damage, and a vicious cycle of injury continues. 

Protease Inhibitors 

We have established that protease activity drives lung injury in AATD, so can protease inhibitors be the therapeutic answer? Unfortunately, clinical studies on protease inhibitors are scarce. For example, a study evaluating an NE inhibitor demonstrated no difference in the sputum neutrophil count between the treatment and the placebo group. 

Commenting on the clinical trials that have investigated the therapeutic properties of protease inhibitors, Fazleen and Wilkson concluded, “Although the studies showed a trend towards clinical/biochemical improvement, they did not always achieve their primary endpoints. It is important to note the short duration of these trials, which may not have been long enough to discern beneficial effects.” 

However, because clinical studies on protease inhibitors are few and far between, it is difficult to make a judgment on their therapeutic efficacy in AATD that holds water. In addition, as mentioned above, many clinical trials that investigate chronic lung conditions such as COPD and bronchiectasis exclude AATD patients.

Read more about AATD treatment 

If medical researchers could be nudged to include AATD in their scope of study, would that make a difference in the number of clinical studies on protease inhibitors available to us? Fazleen and Wilkinson think so.

“Studies directly investigating the role of specific protease activity in AATD, and particularly in various phenotypes of the disease, will enhance understanding of mechanistic pathways in disease development and progression, and will enable development of targeted therapies aimed at different phenotypes of disease,” they wrote. 

“It is possible that, in the future, depending on dominant protease activity, specific protease inhibitors will be appropriate for use in different phenotypes of disease including in AATD.” 

References

Fazleen A, Wilkinson T. The emerging role of proteases in α1-antitrypsin deficiency and beyond. ERJ Open Res. Published online November 22, 2021. doi:10.1183/23120541.00494-2021

Sapey E. Neutrophil modulation in alpha-1 antitrypsin deficiency. Chronic Obstr Pulm Dis. 2020;7(3):247-259. doi:10.15326/jcopdf.7.3.2019.0164