COPD (Chronic obstructive pulmonary disease) is a progressive respiratory condition with major sequelae including cardiovascular risk, respiratory failure, and lung cancer. Several risk factors have been proposed to contribute to COPD, including smoking, indoor and outdoor air pollution, genetics, occupational hazards, and childhood or adult infections. Furthermore, COPD inflicts a large and growing burden in both direct and indirect costs to society. In the United States, COPD costs are projected to increase over the next 20 years, approaching $40 billion per year. Exposure to cigarette smoke, noxious particles, or gases can activate an inflammatory cascade in the airways resulting in the production of a number of potent cytokines and chemokines which play a critical role in the induction of chronic inflammation and subsequent tissue destruction. At a global level, COPD prevalence in 2020, across both males and females, was estimated to be 10.6%, which translates to 480 million cases. 

Ref: Molecular hydrogen is a promising therapeutic agent for pulmonary disease

   Liver disease, encompassing cirrhosis, viral hepatitis, and liver cancer, exacts a substantial toll on global health, claiming millions of lives annually. The intricate interplay of factors, from alcohol consumption to viral infections, underscores the complexity of liver pathology and the imperative for comprehensive interventions. More than 100 million people in the U.S. have some form of liver disease. 4.5 million U.S. adults (1.8%) have been diagnosed with liver disease. Left untreated, liver disease can lead to liver failure and liver cancer.

Liver disease accounts for 2,000,000 deaths annually and is responsible for 4% of all deaths. Approximately 2/3 of all liver-related deaths occur in men. Deaths are largely attributable to complications of cirrhosis and hepatocellular carcinoma. The most common causes of cirrhosis worldwide are related to viral hepatitis, alcohol, and non-alcoholic fatty liver disease.

Ref: Reversal of Liver Fibrosis 

     Chronic kidney disease (CKD) silently afflicts millions worldwide, necessitating heightened awareness and proactive measures for early detection and management. With a staggering prevalence and often asymptomatic nature, CKD poses a formidable challenge in the realm of public health.

CKD is a progressive condition that affects >10% of the general population worldwide, amounting to >800 million individuals. CKD is more prevalent in older individuals, women, racial minorities, and in people experiencing diabetes mellitus, lupus nephritis and hypertension.

CKD represents an especially large burden in low- and middle-income countries, which are least equipped to deal with its consequences. CKD has emerged as one of the leading causes of mortality worldwide. The high number of affected individuals and the significant adverse impact of chronic kidney disease should prompt enhanced efforts for better prevention and treatment.

Ref: New Aspects of Kidney Fibrosis–From Mechanisms of Injury to Modulation of Disease

      Cardiac fibrosis, a hallmark of diverse cardiac pathologies, underscores the critical need for interventions targeting the myocardial microenvironment. As fibrotic alterations compromise cardiac function and precipitate heart failure, strategies aimed at mitigating fibrosis hold promise in enhancing cardiovascular outcomes.

In the heart, the fibrotic scars cause several cardiac dysfunctions either by reducing the ejection fraction due to a stiffened myocardial matrix, or by impairing electric conductance or they can even lead to death. There are several different types of cardiac scars depending on the underlying cause of fibrosis.

Ref: Bioactive Compounds and Cardiac Fibrosis: Current Insight and Future Prospect

     Skeletal muscle fibrosis emerges as a pivotal contributor to muscular dysfunction and vulnerability, presenting formidable obstacles in the management of musculoskeletal disorders. Understanding the intricacies of fibrotic processes in skeletal muscle holds profound implications for therapeutic interventions and rehabilitation strategies.

Skeletal muscle fibrosis impairs muscle function, negatively affects muscle regeneration after injury and increases muscle susceptibility to re-injury, therefore, it is considered a major cause of muscle weakness. Fibrosis of skeletal muscle is a hallmark of muscular dystrophies, aging and severe muscle injuries.

Ref: Inhibition of myostatin reverses muscle fibrosis through apoptosis

     The process of uncontrolled internal scarring, called fibrosis, is now emerging as a pathological feature shared by both peripheral and central nervous system (CNS) diseases.

In the CNS, damaged neurons are not replaced by tissue regeneration, and scar-forming cells such as endothelial cells, inflammatory immune cells, stromal fibroblasts, and astrocytes can persist chronically in brain and spinal cord lesions. Although this process was extensively described in acute CNS damages, novel evidence indicates the involvement of a fibrotic reaction in chronic CNS injuries as those occurring in neurodegenerative diseases such as ALS (Amyotrophic lateral sclerosis), Stroke and MS (Multiple Sclerosis).

ALS: Fibrosis might promote the progression of ALS indirectly by replacing areas of motor neuron loss with excessive scar tissue. 

Stroke: Recent findings suggest that stromal cells infiltrate the ischemic brain, and form a fibrotic scar surrounded by reactive astrocytes.

MS is a neuroinflammatory CNS disease where white matter axonal demyelination, accompanied by the disruption of the blood-brain barrier causes multiple white matter scars in the brain and spinal cord.

Ref: Fibrotic Scar in Neurodegenerative Diseases

     The symbiotic relationship between cancer and fibrosis underscores the multifaceted nature of Tumor Micro-Environments (TME), offering insights into cancer progression, treatment resistance, and therapeutic vulnerabilities.

Some physical and chemical characteristics of TME are :

1) Acidic/ low extracellular pH (may be lower than 6.5); 

2) Tumor fibrosis and inflammation; 

3) Hypoxia (oxygenation deficiency in about 60% of human tumors); 

4) High Interstitial Fluid Pressure (20 to >40 mm/Hg).

TME plays a vital role in protecting cancer cells from drug action in all solid human malignancies. CAFs (cancer associated fibroblasts) promote therapy resistance to cancer cells by enriching the stemness features and promoting the synthesis of ECM (extracellular matrix) components, creating a physical barrier to chemotherapeutic drug action. CAFs have a high tumorigenic potential and can further mediate drug resistance and the proliferation of therapy-resistant cells following drug treatment. ECM deposits constitute up to 60% in tumor mass.

Hydrogen may raise conventional treatments effectiveness by reducing ROS stress in cancerous cells. It helps to improve hypoxia, decrease inflammation/ fibrosis and reduce acidity in TME. Ref:

The double edge sword of fibrosis in cancer

Hydrogen Gas in Cancer Treatment

     Beyond the classical targets of fibrosis, a myriad of organs, including eyes, bone marrow, and skin, are ensnared in the fibrotic cascade, amplifying the burden of chronic diseases worldwide.

Ocular fibrosis is a complex biological process responsible for the pathogenesis or treatment failure of many blinding eye diseases. Diabetic retinopathy, a microvascular complication of both type I and type II diabetes, may progress to sight-threatening stages causing visual impairment and blindness if not well controlled. It´s estimated that diabetic retinopathy is responsible for 4.8% of the 37 million cases of blindness throughout the world.

Globally, the leading causes of vision impairment and blindness are: refractive errors; cataract; diabetic retinopathy; glaucoma and age-related macular degeneration.

Ref: Understanding Drivers of Ocular Fibrosis: Current and Future Therapeutic Perspectives