Mucus in Respiratory Disease

Our respiratory tract secretes mucus into our lungs as an immune defence barrier, clearing out inspired particulates and pathogens by coughing or forced expiration, protecting us from infection [1-3]. In addition to playing an important role in respiratory health, mucus plays an as equally important role in respiratory disease. In healthy people, respiratory mucus is sufficiently hydrated to enable transportation from the deeper respiratory passages up to the trachea for elimination. In disease states, however, changes in mucus composition and hydration status mean that mucus is no longer efficiently eliminated and can become trapped as build-ups in the airways. This leads to inflammation and the formation of mucin plugs [4]. The persistence of mucus plugs in the airways can result in airway dilation and a condition known as bronchiectasis, where damaged airways are no longer able to clear mucus, thus providing an ideal environment for infection and the formation of biofilms: the growth of harmful bacterial and or fungi. This cycle of mucus build up, airway damage, airway inflammation, biofilm formation, commencing in any order, is a characteristic of most respiratory diseases, that can ultimately severely compromise lung function. Acutely, exacerbations of these disease states involve the sudden build up large amounts of mucus in the airways which can lead to serious and even fatal reductions in pulmonary function.

Airway diseases that present these characteristics include:

• Muco-obstructive respiratory diseases  such as some types of Chronic Obstructive Pulmonary Disease (COPD), Non-Cystic Fibrosis Bronchiectasis (NFCB), Cystic Fibrosis (CF) and Primary Cilia Dyskinesia (PCD) [5]. 

• Pneumonia - community or hospital acquired

• Asthma - a disease with muco-obstructive characteristics, but having a different aetiology and pathophysiology [4, 6, 7].

Leading causes of these types of airway diseases include: viral, bacterial and/or fungal infections, damage from smoking, immune-deficiency and genetic predisposition.

How Can Mucpharm Help Respiratory Disease?

Current treatment for these airway diseases, depending on type, include antibiotics, bronchodilators, steroids and mucus thinning and clearing agents as well as their combination. In more severe cases, mechanical ventilation may be required. These treatments, however, often remain suboptimal. Over six million people die from mucus-related chronic respiratory every year [8]. The development of new mucolytic therapies is therefore wanting.

Mucpharm has demonstrated that its lead therapeutic candidate, BromAc® (a highly refined combination of Bromelain and Acetylcysteine), has relevance in providing therapeutic relief for the respiratory diseases described above and preclinical data show it can:

1)     assist the removal of pathological mucus (BromAc®’s mucus-dissolving ability is wide including MUC1, MUC2, MUC5AC, MUC5B, and others)

2)   simultaneously reduce the levels of cytokine and chemokine causing inflammatory molecules (immunomodulatory),

3)   reduce bacterial and fungal infections and destroy associated established biofilms.

Important Milestones in the Development of BromAc® as a Mucolytic in Respiratory Disease

First and importantly, Mucpharm has demonstrated safety of nebulised BromAc® in:

a)  preclinical models including rodent and rabbit, and

b)  healthy volunteers in a hospital setting Phase 1 trial.

Efficacy of BromAc® in clearing/liquifying pathological mucus has been confirmed in:

a)  in vitro studies of collected patient respiratory mucus samples [11, 12]

b)  in vitro studies of artificial mucus created in the laboratory to the characteristics of CF mucus [13]

c) in vitro studies of patient and artificial mucus adhered to both polypropylene tracheal models and patient dervived endotracheal tubes post extubation [13] and ex-vivo ventilated sheep lung model of endotracheal tube obstruction

BromAc® has other mechanisms that are relevant in respiratory conditions including:

• Destroying preformed established biofilms [14]:

a)   as a single agent alone, and

b)  to greater efficacy than BromAc® alone when combined with current first-line antibiotics.

• Reducing the level of inflammation causing and associated molecules know as cytokines and chemokines in:

a)  in vitro cell culture systems, and

b)   in vitro COVID-19 intensive care tracheal aspirate samples [12].

c)  Immunomodulatory and protective effects in an in vivo lipopolysaccharide induced asthma model (not yet published)

• Reduction in viral patient peripheral blood mononucleocyte proinflammatory markers ex vivo [10].

Of note, respiratory cancers such as lung cancer or bronchial invasion of tumours may also benefit from Mucpharm’s therapeutic intervention, and information covering this topic is outlined in the alternate section on Oncology.

Future Development

Mucpharm has obtained Human Research and Ethics Committee approval for a phase 1b/2 in community acquired pneumonia (CAP) admitted to the intensive care unit and expected to be on respiratory support for greater than 72 hours. This study will commence in Brazil with plans to expand to the USA and Australia. A second clinical study (phase 1b/2) is planned in 2024 to address the safety and preliminary efficacy of BromAc in ambulant patients admitted to hospital in Australia with the respiratory conditions including COPD and bronchiectasis.

References

1.             Ridley, C. and D.J. Thornton, Mucins: the frontline defence of the lung. Biochem Soc Trans, 2018. 46(5): p. 1099-1106.
2.            Denneny, E., et al., Mucins and their receptors in chronic lung disease. Clin Transl Immunology, 2020. 9(3): p. e01120.
3.             Rajendran, R.R. and A. Banerjee, Mucus transport and distribution by steady expiration in an idealized airway geometry. Medical Engineering & Physics, 2019. 66: p. 26-39.
4.             Singh, G., et al., Muco-Obstructive Lung Disease: A Systematic Review. Cureus, 2023. 15(10): p. e46866.
5.             Bell, J. and G. Richards, Off-label medicine use: Ethics, practice and future directions. Australian Journal for General Practitioners, 2021. 50: p. 329-331.
6.             Most, J.F., Muco-Obstructive Lung Diseases. N Engl J Med, 2019. 381(10): p. e20.
7.             Boucher, R.C., Muco-Obstructive Lung Diseases. N Engl J Med, 2019. 380(20): p. 1941-1953.
8.             Cohen, M., S.M. Levine, and H.J. Zar, World Lung Day: impact of "the big 5 lung diseases" in the context of COVID-19. Am J Physiol Lung Cell Mol Physiol, 2022. 323(3): p. L338-l340.
9.             Akhter, J., et al., The Combination of Bromelain and Acetylcysteine (BromAc) Synergistically Inactivates SARS-CoV-2. Viruses, 2021. 13(3).
10.          Ferreira, G.M., et al., Taming the SARS-CoV-2-mediated proinflammatory response with BromAc(®).Front Immunol, 2023. 14: p. 1308477.
11.          Coelho Dos Reis, J.G.A., et al., Ex-vivo mucolytic and anti-inflammatory activity of BromAc in tracheal aspirates from COVID-19. Biomed Pharmacother, 2022. 148: p. 112753.
12.          Adeloye, D., et al., Global, regional, and national prevalence of, and risk factors for, chronic obstructive pulmonary disease (COPD) in 2019: a systematic review and modelling analysis. Lancet Respir Med, 2022. 10(5): p. 447-458.
13.          Pillai, K., et al., Effect of Nebulized BromAc on Rheology of Artificial Sputum: Relevance to Muco-Obstructive Respiratory Diseases. Adv Respir Med, 2023. 91(2): p. 146-163.
14.          Carter, C., et al., Dissolution of Biofilm Secreted by Three Different Strains of Pseudomonas aeruginosa with Bromelain, N-Acetylcysteine, and Their Combinations. Appl. Sci. 2021, 11, 11388.