Reduction of Pulmonary In ammation by pH Modi ers

Pulmonary inflammation is a common pathological feature of a variety of diseases, of which successful therapy with currently available anti-inflammatory drugs is limited by resistance and adverse side effects. Using the ovalbumin-induced mouse allergic asthma model, the present study shows that treatments with pH modifiers, particularly simple acids such as acetate or hydrochloric acid, effectively depleted inflammatory cells in the lungs and blood as well as hyperplastic lung tissue cells while preserving the structure of the blood vessels and lung parenchyma. The acid treatments also suppressed mucus hypersecretion. These results demonstrated pH modifiers as a new class of broad-spectrum anti-inflammatory agents with antiproliferation and mucus suppression activities. Introduction Pulmonary inflammation is a common feature of many clinical conditions, most notably asthma, chronic obstructive pulmonary disease (COPD) and acute lung injury, the most severe of which is the acute respiratory distress syndrome (ARDS) of various causes such as viral or bacterial pneumonia, extra pulmonary sepsis and aspiration 1,2 . Not only are these conditions debilitating they can also be fatal. According to a recent report, in 2019 asthma affected about 262 million people and caused 461, 000 deaths, whereas COPD ranked as the No.6 leading cause of disability and caused 3.23 million annual deaths 2-4 . On the other hand, ARDS patients comprised 10% of intensive care unit admissions, and almost 50% of the patients diagnosed with mild to severe ARDS succumbed to this condition 5 . Over zealous local and systemic inflammatory responses that involve both the innate and adaptive arms of the immune system are directly responsible for tissue damages and organ failure in the various diseases with pulmonary inflammation. Therefore, while the ultimate cures and preventive measures targeting the diverse etiologies of these diseases or conditions remain unattainable in the foreseeable future, reduction of inflammation is an important strategy for managing the diseases in both emergency and long-term cares. The mainstay therapy for pulmonary inflammation is corticosteroids (CS). However, CS therapy is limited by resistance and adverse side effects 6-9 . For examples, the benefit of CS therapy of ARDS remains largely inconclusive. 10,11 . Likewise, most COPD patients respond poorly to CS, except very modest reduction of exacerbation 6,12 . The responsiveness of asthma patients to CS therapy is dependent on the endotypes. About 50% of clinical asthma is characterized as Th2-high eosinophilic endotype 13,14 , only a subgroup of which is CS-responsive. Over half of patients with Th2-high asthma, particularly those with severe asthma at old ages, do not respond to CS, and Th2-low asthma endotypes are generally refractory to CS 13,15-18 . CS therapy is further limited by side effects such as osteoporosis, hyperglycemia, increased rate of infections and viral replication 19-23 . Given the limitations of CS due to resistance and side effects, it is of great value to develop alternative anti-inflammatory therapy with the potential of broad applications. This report shows that altering the pH homeostasis in the lungs can effectively deplete inflammatory cells in the lung tissue and lumen while preserving the structure of the blood vessels and lung parenchyma. The findings demonstrate that pH modifiers act as a new class of broad-spectrum anti-inflammatory agents.