The GPCR OGR1 (GPR68) mediates diverse signalling and contraction of airway smooth muscle in response to small reductions in extracellular pH.

BACKGROUND AND PURPOSE: Previous studies have linked a reduction in pH in airway, caused by either environmental factors, microaspiration of gastric acid or inflammation, with airway smooth muscle (ASM) contraction and increased airway resistance. Neural mechanisms have been shown to mediate airway contraction in response to reductions in airway pH to < 6.5; whether reduced extracellular pH (pHo) has direct effects on ASM is unknown. EXPERIMENTAL APPROACH: Intracellular signalling events stimulated by reduced pHo in human cultured ASM cells were examined by immunoblotting, phosphoinositide hydrolysis and calcium mobilization assays. ASM cell contractile state was examined using magnetic twisting cytometry. The expression of putative proton-sensing GPCRs in ASM was assessed by real-time PCR. The role of ovarian cancer G protein-coupled receptor 1 (OGR1 or GPR68) in acid-induced ASM signalling and contraction was assessed in cultures subjected to siRNA-mediated OGR1 knockdown. KEY RESULTS: ASM cells responded to incremental reductions in pHo (from pH 8.0 to pH 6.8) by activating multiple signalling pathways, involving p42/p44, PKB, PKA and calcium mobilization. Coincidently, ASM cells contracted in response to decreased pHo with similar 'dose'-dependence. Real-time PCR suggested OGR1 was the only proton-sensing GPCR expressed in ASM cells. Both acid-induced signalling (with the exception of PKB activation) and contraction were significantly attenuated by knockdown of OGR1. CONCLUSIONS AND IMPLICATIONS: These studies reveal OGR1 to be a physiologically relevant GPCR in ASM cells, capable of pleiotropic signalling and mediating contraction in response to small reductions in extracellular pH. Accordingly, ASM OGR1 may contribute to asthma pathology and represent a therapeutic target in obstructive lung diseases.

Radioimmunodetection of melanoma utilizing In-111 96.5 monoclonal antibody: a preliminary report.

The murine 96.5 monoclonal antimelanoma antibody (MoAb) was labeled with In-111, and 1-20 mg were administered to 21 patients who had proved or suspected melanoma metastases. One patient was studied twice. In four patients, unlabeled 96.5 MoAb was administered prior to the radiopharmaceutical. All of the patients tolerated the procedure without toxicity regardless of the mass of MoAb administered. The scans were interpreted by two observers, one with full knowledge, the other with no knowledge of the cases. Increasing the MoAb mass or preinfusing unlabeled MoAb prior to the administration of In-111 MoAb resulted in a prolongation of the serum half time, and appeared to improve tumor detection. Lesions were best seen at 72 hours after infusion or later. In all patients who had metastatic disease, at least one tumor site was apparent. Fifty-six per cent of known lesions 1.5 cm or greater in size were detected by the physician who had knowledge of the cases when data from all doses were considered. There were eight lesions detected that were not suspected in the workup of the patient. When these are included, the detection rate rises to 61%. Forty-nine per cent were detected by the other physician. Subtraction techniques were not employed. Lesions were often better seen with single photon emission computed tomography than with planar imaging techniques. The 96.5 In-111 MoAb appears to have utility for the detection of metastatic melanoma. Further clinical evaluation of 96.5 In-111 MoAb is warranted.

Infantile acropustulosis.

Infantile acropustulosis (IA) is a syndrome characterized by recurrent crops of 1- to 2-mm intensely pruritic vesicopustules that are found primarily on the distal extremities of infants. It is reportedly responsive to sulfones and unresponsive to other therapy, but if left untreated spontaneously resolves at about 2 years of age. It is more common in black male patients. The histopathologic findings and clinical course are distinct.

Erythema chronicum migrans in the United States.

Four cases of erythema chronicum migrans occurred within a one-month period in southeastern Connecticut. The syndrome may include advancing erythematous rash stemming from an apparent insect bite, hyperesthesias, myalgias, malaise, fever, lymphadenopathy, and, rarely, meningitis. Treatment with penicillin, the tetracycline, or, in our experience, erythromycin usually results in prompt resolution.

Inhibition of induction of human contact sensitization by topical glucocorticosteroids.

Ten healthy human volunteers were exposed to a primary sensitizing dose of 1 mg dinitrochlorobenzene (DNCB) by an open topical technique within an area that had been pretreated with a potent topical glucocorticosteroid compound. Quantitative elicitation testing was performed on the opposite side by an open patch test technique two weeks after the sensitizing application. One (10%) of the ten subjects became sensitized. A matched control group of ten subjects was similarly sensitized without steroid treatment. Eight (80%) of the ten became sensitized. One month later, five of the eight test subjects in whom sensitization had been prevented were retested in an identical fashion without steroid pretreatment, to determine if any degree of tolerance had been induced. All five subjects became sensitized. Topical glucocorticosteroids inhibited the development of sensitization to topically applied DNCB. Tolerance was not induced by this single process.