ABSTRACT
Bilateral hindlimb paresis occurred in 3 guinea pigs after immunization with an adjuvant-antigen mixture containing complete Freund's adjuvant. Doses were injected into unanaesthetized animals, divided among 3 or 4 sites, and given slightly off midline in the subcutaneous tissues of the back. Neurologic examination of affected animals revealed intact flexor and panniculus responses and limited voluntary movement of the hindlimbs. Histopathologic interpretation of 2 affected animals showed fibrogranulomatous material effacing the skeletal muscle and vertebral bone, with marked bone lysis and infiltration into the marrow space and spinal canal. In addition, multiple granulomas in the pulmonary parenchyma were noted. A postmortem radiograph of the excised thoracolumbar spine of 1 animal revealed a soft tissue swelling and "moth-eaten" and geographic osteolysis of 2 spinous processes. Hindlimb paresis and osteolysis likely resulted from accidental injection of the adjuvant-antigen mixture into the epaxial musculature and subsequent extension of injection site granulomas into the spinal canal.
Subject(s)
Adjuvants, Immunologic/adverse effects , Freund's Adjuvant/adverse effects , Guinea Pigs , Osteolysis/veterinary , Paresis/veterinary , Rodent Diseases/etiology , Animals , Animals, Laboratory , Female , Freund's Adjuvant/administration & dosage , Granuloma/complications , Granuloma/veterinary , Hindlimb/physiopathology , Injections, Subcutaneous/veterinary , Movement , Osteolysis/diagnosis , Osteolysis/etiology , Paresis/diagnosis , Paresis/etiology , Radiography , Spinal Canal/pathology , Spine/diagnostic imaging , Spine/pathologyABSTRACT
The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated chloride channel localized primarily at the apical or luminal surfaces of epithelial cells that line the airway, gut, and exocrine glands; it is well established that CFTR plays a pivotal role in cholera toxin (CTX)-induced secretory diarrhea. Lysophosphatidic acid (LPA), a naturally occurring phospholipid present in blood and foods, has been reported to play a vital role in a variety of conditions involving gastrointestinal wound repair, apoptosis, inflammatory bowel disease, and diarrhea. Here we show, for the first time, that type 2 LPA receptors (LPA2) are expressed at the apical surface of intestinal epithelial cells, where they form a macromolecular complex with Na+/H+ exchanger regulatory factor-2 and CFTR through a PSD95/Dlg/ZO-1-based interaction. LPA inhibited CFTR-dependent iodide efflux through LPA2-mediated Gi pathway, and LPA inhibited CFTR-mediated short-circuit currents in a compartmentalized fashion. CFTR-dependent intestinal fluid secretion induced by CTX in mice was reduced substantially by LPA administration; disruption of this complex using a cell-permeant LPA2-specific peptide reversed LPA2-mediated inhibition. Thus, LPA-rich foods may represent an alternative method of treating certain forms of diarrhea.
