Indeed, the LTE4 concentrations needed to activate CysTR1 and CysLTR2 may be higher than those that normally occur in vivo (see Functions of OXGR1 in mediating the actions of LTE4, LTD4, and LTC4).
Second, LTE4 was as potent as LTC4 and LTD4 in eliciting vascular leakage when injected into the skin of guinea pigs and humans; the inhalation of LTE4 by asthmatic individuals caused the accumulation of eosinophils and basophils in their bronchial mucosa whereas the inhalation of LTD4 did not have this effect; and mice engineered to lack CysLTR1 and CysLTR2 receptors exhibited edema responses to the intradermal injection of LTC4, LTD4, and LTE4 but LTE4 was 64-fold more potent in triggering this response in these mice than in wild type mice.
[29] The following studies have defined OXGR1 functions based on the presence of disorders in mice or humans that do not have a viable OXGR1 protein.
Mice lacking OXGPR1 protein due the knockout of their OXGR1 gene developed (82% penetrance) otitis media (i.e., inflammation in their middle ears), mucus effusions in their middle ears, and hearing losses all which had many characteristics of human otitis media.
(Infection with Streptococcus pneumoniae, Moraxella catarrhalis, or other bacteria is one of the most common causes of otitis media.
[30]) While the underlying mechanism for the development of this otitis has not been well-defined, the study suggests that OXER1 functions to prevent middle ear inflammations and Oxgr1 gene knockout mice may be a good model to study and relate to human ear pathophysiology.
The study proposed that the OXGR1 gene is a candidate for functioning to suppress the development of calcium-containing nephrolithiasis and nephrocalcinosis in humans.
These functions include: promoting normal kidney functions such as the absorption of key urinary ions and maintenance of acid base balance;[33] regulating the development of glucose tolerance as defined by glucose tolerance tests;[34] suppressing the development of diet-induced obesity;[35] and suppressing the muscle atrophy response to excessive exercise.
[35] A study showed that LTE4, LTC4, and LTD4 produce similar levels of vascular leakage and localized tissue swelling when injected into the skin of guinea pigs or humans.
The study concluded that lower levels of LTE4 act primarily through OXGR1 to cause vascular permeability and, since it is the major cysteinyl leukotriene that accumulates in inflamed tissues, suggested that OXGR1 may be a therapeutic target for treating inflammatory disorders.
[5] Another study found that the application of an extract of Alternaria alternata (a genus of fungi that infects plants and causes allergic diseases, infections, and toxic reactions in animals and humans[36]) into the noses of mice caused their nasal epithelial cells to release mucin and their nasal submucosa to swell.
[37] Control mice that inhaled the mold Alternaria alternata, the American house dust mite Dermatophagoides farinae, or LTF4 developed increases in the number of their tracheal brush cells, release of the inflammation-promoting cytokine, interleukin 25, and lung inflammation whereas OXGR1 gene knockout mice did not show these responses.
These findings indicate that the activation of OXGR1 regulates airway: brush cell numbers, interleukin 25 release, and inflammation.
This study showed that itaconate stimulated the nasal secretion of mucus when applied to the noses of mice, reduced the number of Pseudomonas aeruginosa bacteria in their lung tissue and bronchoalveolar lavage fluid (i.e., airway washing) in mice injected intranasally with these bacteria, and stimulated cultured mouse respiratory epithelium cells to raise their cytosolic Ca2+ levels (an indicator of cell activation).
The study concluded that the activation of OXGR1 by itaconate contributes to regulating the pulmonary innate immune response to Pseudomonas aeruginosa and might also do so in other bacterial infections.
[8][16] This article incorporates text from the United States National Library of Medicine, which is in the public domain.