Infiltrating microbes’ express pathogen-associated molecular patterns (PAMPs) and cause injury to the lung’s functional tissues (parenchyma). Parenchymal cells then release damage-associated molecular patterns (DAMPs) and alarmins to alert the immune system. In order to protect and preserve lung function, the immune system activates residential macrophages; which produce a large number of inflammatory chemokines and cytokines, attract circulating immune cells in the lungs and initiate inflammation ^[2].

Inappropriate immune responses and/or aberrant repair process (sepsis) causes irreversible damage in lung tissue and most usually results in the development of fibrosis followed by a decline in lung function ^[3]. Clinically, acute lung injury (ALI) and inflammation are seen in pneumonia and acute respiratory distress syndrome (ARDS) ^[4,5]. Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common complications following sepsis, pulmonary contusion, inhalational injury, and near-drowning ^[6,7]. Chronic inflammation is represented by asthma and chronic obstructive pulmonary diseases (COPD); which include emphysema and chronic bronchitis ^[4,8].   

Generic injury to the lung results in damage to the epithelial and endothelial cells and a compromised alveolar-capillary barrier. The progression of acute lung injury to fibrosis portends a poor prognosis and may be observed as early as 5 to 7 days after injury ^[9].

Lung disease may be divided into 2 categories:

Restrictive lung disease is characterized by reduced lung volumes and therefore reduced lung compliance ^[10]. It becomes difficult for the lungs to expand completely, making it harder for someone to inhale fully ^[11] either due to an:

• Intrinsic reason: Diseases of the lung parenchyma that cause the lung tissues to become inflamed or scarred or a disease that causes the alveoli air spaces to be filled with external material ^[10]. These are diseases such as interstitial lung disease (ILD); which may progress to idiopathic pulmonary fibrosis (IPF), pulmonary fibrosis, pneumonia, acute respiratory distress syndrome (ARDS), sarcoidosis and pneumoconiosis such as silicosis ^[11].

• Extrinsic reasons: Diseases of the chest wall, pleura, or respiratory muscles that result in lung restriction, impaired ventilatory function, and even respiratory failure due to a disease that affects the lungs’ ability to create a change in lung volumes during respiration ^[10]. These are diseases such as scoliosis, a build-up of fluid around the lungs, some autoimmune diseases; such as myasthenia gravis; and some neuromuscular diseases; such as muscular dystrophy ^[11].

Obstructive lung disease is characterised by narrowing of the smaller bronchi and larger bronchioles, often because of excessive contraction of the smooth muscle itself. It is generally characterized by inflamed and easily collapsible airways and obstruction to airflow ^[12]. This interferes with the ability of the lungs to exhale air fully ^[11]. Types of obstructive lung disease include; asthma, bronchiectasis, bronchitis, chronic obstructive pulmonary disease (COPD); such as emphysema and chronic bronchitis; and cystic fibrosis ^[12,13].

How Our Products Can Treat Lung Diseases

We use products derived from human baby umbilical cords in all our therapy programs - Wharton's Jelly MSCs (wjMSCs). MSCs, in general, are special because they can:

• modulate inflammation/immune response ^{[14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,46,47,48,49,50]}.
• restore and preserve pulmonary alveolar architecture ^{[14,21,22,33,34,47,50]}.
• differentiate into functional cells ^{[16,17,31,34,35,36]}.
• repair and prevent formation of fibrosis ^[18,31,37].
• decrease collagen deposition ^{[16,30,38,46]}.
• reduce or prevent pulmonary oedema ^[22,23,32,].
• home to site of injury (chemotaxis) ^{[16,19,23,31,32,33,35,36,39,40]}.
• incapable of forming tumours ^{[7,8,14,15,16,41,42,43,44,45]}.

Treating Lung Diseases

There are currently numerous clinical trials exploring the use of wjMSCs in the treatment of lung diseases. These have been registered but results and findings have yet to be posted ^{[51,52,53,54,55,56,57,58,59,60,61,62,63,64,65]}.

Interstitial Lung Disease (ILD) / Idiopathic Pulmonary Fibrosis (IPF)

Pulmonary fibrosis occurs as a wound-healing process after many forms of pulmonary injury that are induced by a variety of factors. However, chronic inflammation and pulmonary fibrosis can be developed without any known causes in certain cases. That is classified as idiopathic interstitial pneumonias (IIPs) ^[66].

Between June of 2010 and September of 2011, a study was conducted to evaluate incidents of treatment-emergent adverse events within 12 months. 14 IPF patients received 500,000 of their own (autologous) adipose MSCs (adMSCs) per kilogram of body weight once a month for 3 months (total of 1.5 million adMSCs by the end of the study). No cases of serious or clinically meaningful adverse events were recorded in all patients. Detailed safety monitoring through several time-points (baseline, 6 and 12 months after the first infusion) indicated that cell-treated patients did not deteriorate in functional parameters and experienced improved quality of life ^[67].  

A study published in 2017, divided 9 IPF patients into groups of 3. Each group received a single intravenous (I.V.) infusion of, either, 20, 100 or 200 million donor (allogeneic) bone marrow MSCs from 9 unrelated young men. Safety, secondary efficacy endpoints and disease progression were assessed every 28 days for 60 weeks after treatment. No treatment-emergent serious adverse events were reported. At 60 weeks post-infusion, there was a slower mean decline of 3.0% in predicted forced ventilation capacity (FVC) and slower mean decline of 5.4% in predicted diffusing capacity of the lung for carbon monoxide (DLCO) ^[68].

In 2019, the results of a study involving 20 patients with rapidly progressing idiopathic pulmonary fibrosis (IPF), of whom only 16 completed the study, were published. They were randomized into 2 groups of 10 patients each: a treatment group and a placebo group. The 10 patients in the treatment group received 200 million allogeneic bmMSCs over the course of 39 weeks (a total of 1.6 billion allogeneic over 8 sessions). At the same time, the placebo group was given saline solution. Improvements were noted as early as 3 months post-treatment. 12 months post-infusion; the treatment group saw a 26.6% increase in the 6‐minute walk test difference (6MWTD) while the placebo group saw a 9.8% decrease, a 3.7% increase in forced ventilation capacity (FVC) while the placebo group saw a 9.5% decrease and a slower decline (-5.1%) in diffusing capacity of the lung for carbon monoxide (DLCO) while the placebo group saw a more prominent decline (-12.9%) ^[69].

Acute Respiratory Distress Syndrome (ARDS)

Acute lung injury and acute respiratory distress syndrome (ARDS) are life-threatening conditions characterised by acute lung inflammation-causing pulmonary congestion, hypoxaemia, and decreased pulmonary compliance ^[70].

Between January and April 2013, 12 ARDS patients were shortlisted for participation in a clinical trial. Patients were divided into 2 groups and received either 1 intravenous (I.V.) dose of 1 million allogeneic adMSCs per kilogram of body weight or saline. For 28 days after infusion, acute lung injury biomarkers; such as interleukin-6 (IL-6), interleukin-8 (IL-8) and surfactant protein D (SP-D), were examined to determine the effects of MSCs on lung injury and inflammation. Significant improvements in oxygenation index (PaO2/FiO2) were observed in all data points (Day 1, 3, 5, 7, 14, 28) in the MSCs group. Serum SP-D levels at Day 5 were significantly lower than those at Day 0 (p = 0.027). IL-6 levels at Day 5 showed a trend towards lower levels as compared with Day 0. The mean value for IL-8 at Day 5 was also much lower than that of Day 0 ^[71].

A Taiwanese study published in 2020 treated 9 ARDS patients with differing doses of allogeneic human umbilical cord MSCs (wjMSCs). Between December 2017 and July of 2019;

• 3 patients received a low-dose of 1 million wjMSCs per kilogram of body weight,
• 3 patients received an intermediate dose of 5 million wjMSCs per kilogram of body weight while
• the final 3 patients received a high dose of 10 million wjMSCs per kilogram of body weight.

No serious pre-specified cell infusion-associated or treatment-related adverse events were identified in any of the patients. Serial flow-cytometric analyses of circulating inflammatory biomarkers were notably and progressively reduced whereas the immune cell markers were notably increased after infusion ^[72].

Sarcoidosis

Sarcoidosis is a systemic non-necrotizing granulomatous disease, the aetiology of which is suspected to be immune-mediated ^[73].

Ginoux et al. treated a 55-year-old woman who had a 2-year history of joint pain and several episodes of uveitis. Physical examinations and laboratory findings confirmed a diagnosis of lichenoid sarcoidosis. 8 years after the diagnosis, bone marrow biopsy concluded primitive myelofibrosis progressing to acute myeloid leukaemia (AML). After non-ablative conditioning, the patient was given allogeneic umbilical cord blood MSCs (ucbMSCs). Upon completion of treatment, the patient was asymptomatic and full remission was obtained for both AML and sarcoidosis. 2 months after treatment, the patient presented with cutaneous graft-versus-host disease (GvHD) which was well controlled using mycophenolate mofetil and everolimus for 3 months. 5 months after MSC treatment, all immunosuppressive drugs were stopped without any recurrence of sarcoidosis, which, after 4 years of follow-up, remains asymptomatic ^[74].

Pneumoconiosis / Silicosis

Pneumoconiosis is an occupational lung disease caused by breathing in particles of mineral dust. It is a form of interstitial lung disease and silicosis is the most common type of pneumoconiosis globally. The industrialization process has steadily increased the occupational hazards of workers to airborne particles in many work environments. It occurs when an irritant is inhaled and then settles in the lungs leading to inflammation which causes irreversible scarring to the tissue. Over time, this causes the lungs to harden and interferes with the lung’s normal exchange of carbon dioxide and oxygen. Among these particles, silicon dioxide; or silica; plays an important role in occupational-acquired respiratory diseases. Inhalation of silica particles causes silicosis: a persistent inflammation with granuloma formation that leads to tissue remodelling and impairment of lung function ^[75,76].

A 2015 Brazilian study, 20 million autologous bone marrow-derived mononuclear cells (bmMCs) were instilled in the bronchi of 5 silicosis patients using fibre-optic bronchoscopy. Patients were followed-up for a year post-transplantation. The procedure was well tolerated and no adverse events were observed in the follow-up period. The bmMCs transplantation seems to have led to an early increase in perfusion at the base of both lungs, which remained increased for the duration of the follow-up in all 5 patients ^[77].

That same year, a Chinese study published the results of their clinical trial of treating 4 silicosis patients with autologous bone marrow MSCs (bmMSCs) and hepatocyte growth factor (HGF). 2 million bmMSCs per kilogram of body weight were administered intravenously once a week for 3 consecutive weeks. The treatment was found to be generally safe. Symptoms such as cough and chest distress gradually ameliorated at 6 months post-therapy. This was accompanied by a significant improvement in pulmonary function. The ratios of the peripheral lymphocyte (CD4- and CD8-) positive cell concentrations were increased. Serum immunoglobulin G (IgG) levels in these patients were decreased and reached the normal range while CT scans showed partial absorption of the nodular and reticulonodular lesions in the lungs during follow-up of at least 12 months ^[78].

Allergic Asthma

Allergic asthma is characterized by airway hyper-responsiveness (AHR) to a variety of specific and nonspecific stimuli, chronic pulmonary eosinophilia, elevated serum immunoglobulin E (IgE) and excessive airway mucus production ^[79,80,81]. MSCs have not been explored as a treatment option for asthma in humans. However, numerous studies have found that MSCs are able to treat mouse models of asthma with considerable success.

Cruz et al. published 2 animal model studies in 2015. In both studies, mice were first exposed to irritants to deliberately induce asthmatic conditions then treated with MSCs. In the first study, the mice were treated with either conditioned media (CM) or extracellular vesicles (EVs) derived from either mice or human bone marrow MSCs (bmMSCs) at the onset of asthma symptoms. In their second study, they found that efficacy did not differ between freshly thawed human bmMSCs and freshly cultured human bmMSCs. Both studies found that human bmMSCs ameliorated airway hyper‐reactivity, lung inflammation and antigen‐specific CD4 T‐cell Th2 and Th17 phenotype in a mouse model of allergic asthma ^[82,83].

In 2017, a Brazil study investigated the potentials of mouse MSCs from different sources; bone marrow (bmMSCs), adipose tissue (adMSCs) and lung tissue MSCs (ltMSCs); in the treatment of asthma in mice. As with the previous study, mice were first exposed to irritants to deliberately induce asthmatic conditions then injected in the spine with 100,000 MSCs.  The study found that bmMSCs, adMSCs and ltMSCs differentially effective at reducing airway inflammation and remodelling as well as improving lung function while reducing inflammation and fibrogenesis ^[84].

Chronic Obstructive Pulmonary Disease (COPD)

The key pathologic changes underlying the physiological hallmarks of COPD include the loss of lung elasticity and small airway tethers (emphysema), thickening of the small airway wall to reduce calibre and luminal obstruction with inflammatory mucoid secretions ^[85]. Subcategories of COPD include chronic bronchitis (obstruction of small airways) and pulmonary emphysema.

Chronic bronchitis is characterized by hyper-secretion of mucus accompanied by a chronic (more than 3 months in 2 consecutive years) productive cough; infectious agents are a major cause.

The main feature of pulmonary emphysema is airflow obstruction due to destruction of the alveolar walls distal to the terminal bronchiole, without significant pulmonary fibrosis. Most COPD patients have chronic bronchitis and pulmonary emphysema, together with mucus plugging; however, the severity varies between individuals ^[86].

In 2013, an American study treated 62 patients suffering from emphysema and chronic bronchitis. 31 patients received allogeneic bone marrow MSCs (bmMSCs) while the remaining 31 were given saline solution and served as the placebo group. Each patient in the treatment group received 100 million bmMSCs on Days 0, 30, 60, and 90. All participants were subsequently evaluated for safety and efficacy for 2 years after the first infusion. Post-hoc analysis of; 14 patients in the MSC group vs. 15 patients in the placebo group; all 29 of whom had elevated circulating C-reactive protein (CRP) levels at the beginning of the study demonstrated a statistically significant decrease in circulating CRP at 1 month after the first infusion in the 14 patients from the MSC group only. This numerical trend continued for the duration of the study and the evaluation period ^[87].

That same year, Stessuk et al. published the findings of their study involving 4 advanced pulmonary emphysema patients. All patients received an infusion of autologous bone marrow mononuclear cells (bmMCs) and follow-ups were performed by spirometry up to 3 years after the procedure. They found that bmMC therapy in patients suffering from COPD to be safe and free of adverse effects. There was an improvement in laboratory parameters (spirometry) and a slowing in the process of pathological degeneration. Patients reported improvements in clinical conditions and quality of life as well ^[88]. This corroborated the findings of an identical 2011 study of 4 advanced pulmonary emphysema patients by Ribeiro-Paes et al. who also reported significant improvement in the quality of life, as well as a clinically stable condition, which suggested a change in the natural process of the disease by the end of the 12-month study ^[89].

A 2016 study explored performing lung volume reduction surgery (LVRS) followed by autologous bone marrow MSCs (bmMSCs) in 7 patients who had emphysema in both upper lung lobes with an equal distribution pattern in both lungs. All patients had stopped smoking 6 months before treatment commencement. All patients received 2 intravenous (I.V.) infusions of 1 to 2 million bmMSCs per kilogram of body weight 1 week apart. The study found that forced expiratory volume in one second (FEV¹) was increased and residual volume decreased compared to baseline. The difference in CT-derived lung density at 15th percentile point (Perc15) obtained from a chest CT-scan prior to the first LVRS and one year after the second LVRS was 7.3 ± 4.3 gr/L (p = 0.013). These results are comparable to our results reported previously. The number of CD31+ (endothelial cells), CD4+ T cells, CD3+ T cells, interleukin-10 (IL10) and TNF-stimulated gene-6 (TSG6) levels had significantly increased possibly indicating protective and/or repair responses against further tissue destruction. All patients had gained, on average, 4.6 kilograms in weight since the beginning of the study ^[90].