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Perfluorochemical (PFC) emulsions are particulate in nature and, as such, can cause delayed febrile reactions when injected intravenously. This study investigated the influence of emulsion particle size on intravascular retention and on body temperature changes in unrestrained conscious rats. Concentrated (60% to 90% w/v) emulsions based on perflubron (perfluorooctyl bromide [PFOB]) with mean particle sizes ranging from 0.05 microns to 0.63 microns were tested. Rats were fitted with a chronic jugular catheter and an abdominal body temperature telemetry unit. Fully recovered, conscious rats were monitored for 24 hours after infusion (dose = 2.7 g PFC/kg). Emulsion blood half-life (T1/2) was determined from blood perflubron levels measured by gas chromatography. Emulsions with a particle size of 0.2-0.3 microns caused fevers (6 to 8 hour duration) which peaked at 1-1.5 degrees C above normal (approximately 37.5 degrees C). Fevers could be blocked by i.v. treatment with either cyclooxygenase inhibitors (ibuprofen) or corticosteroids (dexamethasone). Both intensity and duration of the temperature response, quantified by area under the temperature curve, was decreased significantly for emulsions with a particle size < or = 0.12 micron. Blood T1/2 varied inversely with particle size, and was 3 to 4 fold longer for emulsions with a mean particle size < or = 0.2 micron. Thus, smaller emulsion particles more effectively evaded the reticuloendothelial system, which resulted in longer intravascular retention, less macrophage activity, and reduced febrile responses.

A challenging aim in developing injectable fluorocarbon emulsions is to combine good flow characteristics (especially at low shear rates) with the high fluorocarbon concentration required for high oxygen delivery or effective contrast in imaging, long shelf life, and biological acceptability. A good balance of these sometimes conflicting objectives has been achieved with 90% w/v concentrated emulsions of various fluorocarbons, including the radiopaque oxygen carrier perfluorooctylbromide (PFOB, perflubron). The sterile emulsions have viscosities of about 20 cPs at a shear rate of 1 sec-1; the viscosity decreases rapidly with fluorocarbon concentration, and at 60% w/v the viscosity is less than that of human blood. The emulsions are suitable for injection as prepared, and are stable unfrozen for over a year.

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Disruption of alveolar type 2 cell (AEC2) protein quality control has been implicated in chronic lung diseases, including pulmonary fibrosis (PF). We previously reported the in vivo modeling of a clinical surfactant protein C (SP-C) mutation that led to AEC2 endoplasmic reticulum (ER) stress and spontaneous lung fibrosis, providing proof of concept for disruption to proteostasis as a proximal driver of PF. Using two clinical SP-C mutation models, we have now discovered that AEC2s experiencing significant ER stress lose quintessential AEC2 features and develop a reprogrammed cell state that heretofore has been seen only as a response to lung injury. Using single-cell RNA sequencing in vivo and organoid-based modeling, we show that this state arises de novo from intrinsic AEC2 dysfunction. The cell-autonomous AEC2 reprogramming can be attenuated through inhibition of inositol-requiring enzyme 1 (IRE1α) signaling as the use of an IRE1α inhibitor reduced the development of the reprogrammed cell state and also diminished AEC2-driven recruitment of granulocytes, alveolitis, and lung injury. These findings identify AEC2 proteostasis, and specifically IRE1α signaling through its major product XBP-1, as a driver of a key AEC2 phenotypic change that has been identified in lung fibrosis.

Experimental observations are consistent with the proposed theory of perfluorocarbon-related gas osmosis through micro-bubbles that prevent complete lung collapse as observed upon opening the thoracic cavity of test animals.

In this study, the effects of formulation, processing and storage parameters on perflubron (perfluorooctyl bromide; PFOB) emulsions were investigated. Emulsions with varying concentrations of perflubron and egg yolk phospholipid (EYP) were prepared with different processing parameters and placed at different storage temperatures. Their characteristics and stability were compared. The emulsion droplet growth rate was nearly proportional to the perflubron percentage in the range of 15-110% w/v. The initial droplet size of perflubron emulsions was inversely proportional to the concentration of EYP until a certain lower limit of droplet size was reached. The initial droplet size and droplet growth rate of perflubron emulsion were strongly dependent upon the processing parameters. The logarithmic value of the droplet growth rate decreased linearly with l/T in the range of 5-40 degrees C. The formulation and processing parameters are the key variables to be optimized to achieve better emulsion characteristics and stability.