General

Secretoglobins (SCGBs) are naturally occurring proteins produced in the body by various organs. The SCGBs produced in the lungs are some of the most abundant proteins secreted in the airways. Naturally occurring SCGB1A1 is the most abundant protein in the fluid that lines the respiratory tract, including the nasal airways. These proteins modulate inflammatory and immunologic responses to the environment on mucosal surfaces throughout the body.

Respiratory tract damage and lung impairment can be caused by numerous insults, including infectious pathogens, allergens, dust or smoke, chemicals, noxious gases, inert particles, and many other potential irritants. When lungs are exposed to these insults, an inflammatory response is triggered, which often causes more physical damage to the lungs, leading to acute lung injury, loss of lung function, and/or long term fibrosis.

Many patients with acute and chronic respiratory conditions are deficient in their own SCGB1A1 production due to a lack of specialized airway epithelial cells, called Club cells, that populate normal airways and produce SCGB1A1. In recurrent acute and chronic rhinosinusitis, the nasal airway cells that produce SCGB1A1 are replaced by fibrotic cells and scar tissue, resulting in a deficiency of SCGB1A1 and Club cells which pre-disposes patients to persistent infections and further scarring, eventually requiring sinus surgery. Similarly, in acute lung injury due to influenza-like illness, smoke inhalation, or sepsis, the normal lung epithelial cells are damaged, resulting in loss of local SCGB1A1 production. The administration of Therabron in these conditions can reduce viral load, reduce inflammation, protect lung function, stimulate airway repair, reduce pulmonary edema and reduce fibrosis in the lungs. In COPD, there is also a well-characterized deficiency of Club cells and SCGB1A1, also called CC16, in the lungs. Many other respiratory conditions have also been associated with a deficiency of Club cells and native SCGB1A1. Therabron may prove to help alleviate the cascade of potential injuries through its anti-inflammatory effects as well as its potential to stimulate lung repair.

Impact on Lung Inflammation

At least four distinct pathways are affected by SCGB1A1 and  Therabron:

1) Phospholipase A2 (PLA2) are enzymes found in many tissues that catalyze the hydrolysis of glycerophospholipids to release arachidonic acid (AA). AA is a substrate for a variety of other enzymes that lead to the formation of eicosanoid mediators of inflammation, such as leukotrienes, which have been linked to development of neonatal lung disease and are associated with severity and progression of chronic lung diseases in adults, including COPD and asthma. SCGB1A1 and SCGB3A2 inhibit PLA2 enzymes.

2) The influx of neutrophils to the lungs of individuals with Acute Lung Injury (ALI) or with chronic lung disease contributes to life-threatening inflammation and loss of lung function and is strongly inhibited by Therabron. Likewise, pro-inflammatory cytokines that are released in ALI, attract neutrophils and other white cells, and further enhance inflammation and tissue damage, including IL-4, IL-5, IL-6, IL-8, IL-13, TNF-α, IL1β, and others, are all strongly inhibited by Therabron.

3) Nuclear factor kappa B (NF-κB) is a master molecular switch that can turn on multiple inflammatory pathways in the lung and in many other tissues. NF-κB normally maintains a low level of activity, but when a cell experiences an insult or receives a pro-inflammatory signal from another cell, NF-kB is activated, translocates into the cell nucleus, and increases the transcription of additional pro-inflammatory regulators. Native SCGB1A1 and Therabron suppress the activation of NF-κB, both in vitro and in vivo and thereby suppresses inflammation and the fibrosis caused by triggering of the NF-κB signal transduction pathway.

4) Another aspect associated with ALI, severe smoke inhalation, sepsis, and shock is increased vascular permeability, which results in pulmonary edema and/or shock. Pulmonary edema and shock are life-threatening conditions with limited treatment options at this time. Therabron has demonstrated that it suppresses fluid accumulation, pulmonary edema, and shock due to ALI.