AKI affects both quality of life and health care costs and is an independent risk factor for mortality. At present, there are few effective treatment options for AKI. Here, we describe a nonpharmacologic, noninvasive, ultrasound-based method to prevent renal ischemia-reperfusion injury in mice, which is a model for human AKI. We exposed anesthetized mice to an ultrasound protocol 24 hours before renal ischemia. After 24 hours of reperfusion, ultrasound-treated mice exhibited preserved kidney morphology and function compared with sham-treated mice. Ultrasound exposure before renal ischemia reduced the accumulation of CD11b+Ly6Ghigh neutrophils and CD11b+F4/80high myeloid cells in kidney tissue. Furthermore, splenectomy and adoptive transfer studies revealed that the spleen and CD4+ T cells mediated the protective effects of ultrasound. Last, blockade or genetic deficiency of the α7 nicotinic acetylcholine receptor abrogated the protective effect of ultrasound, suggesting the involvement of the cholinergic anti-inflammatory pathway. Taken together, these results suggest that an ultrasound-based treatment could have therapeutic potential for the prevention of AKI, possibly by stimulating a splenic anti-inflammatory pathway.

Ultrasound Prevents Renal Ischemia-Reperfusion Injury by Stimulating the Splenic Cholinergic Anti-Inflammatory Pathway

5 – Effects and Mechanisms

Kremkau wrote a historical review of the use of ultrasound in cancer therapy in 1979(1) In 1990, Kondo and Kano published a Japanese review of the implications of the thermal and nonthermal effects of ultrasound in the treatment of cancer2). Again in 2000, Kondo et al reviewed the therapeutic applications of ultrasound and shock wave, emphasizing their thermal and cavitational effects3). Here we focus on the effects of ultrasound or shock waves in combination with anticancer agents, emphasizing their mechanisms of action and interaction. Most of the studies cited here reported promising results. Although the extent of the augmented combined effects in vivo is limited, synergism is the rule in vitro. In addition to the thermal effect of ultrasound, cavitational effects undoubtedly played a major role in both ultrasound and, more prominently, in shock wave therapy. Although the mechanism of the nonthermal noncavitational effects on biological processes is obscure, several factors, including temperature and the occurrence of cavitation and inertial cavitation, probably coexist and blend with these other effects. Magnification of anticancer activity results mainly from increased localization of drugs or other agents in vivo and increased intracellular permeabilisation both in vivo and in vitro. On the other hand, sublethal damage caused by ultrasound or shock waves may render cells more susceptible, to the effects of the agents, and both may act together, further amplifying these effects. We thus conclude that proper combination of an appropriate agent and ultrasound or shock wave should help improve cancer therapy by minimizing the side effects of drugs by lowering the effective dose and reducing the systemic concentration while increasing the efficiency of the therapy as a whole. Future studies should reveal specific conditions in this combined therapy that will lead to optimal outcome.

Sound waves and antineoplastic drugs: The possibility of an enhanced combined anticancer therapy

The theoretical possibility that exposure of a solid malignancy to high-intensity focused ultrasound (US), or HIFU, could lead to an increased rate of metastasis still remains. Using reverse transcriptase polymerase chain reaction (RT-PCR), the potential risk of hematogenous dissemination was assessed in HIFU-treated patients with solid malignancy. RT-PCR can demonstrate the presence or absence of specific RNA fragments. On the day before HIFU ablation, 5-mL peripheral blood samples were collected, and again 5 to 7 days after HIFU, from 26 enrolled patients (hepatocellular carcinoma, HCC: 10; osteosarcoma: 16). Total RNA was isolated and RT-PCR was performed to analyze the mRNA expression of (α-fetoprotein (AFP) and bone-specific alkaline phosphatase (BALP) genes. Positive AFP mRNA expression was preoperatively detected in 8 of 10 patients with HCC. In the postoperative specimens, positive expression was also detected in 8 of 10 patients. In 2 patients, circulating tumor cells were found preoperatively, but not postoperatively. Conversely, 2 patients with no circulating tumor cells preoperatively were found to have circulating tumor cells after HIFU. Of 16 osteosarcoma patients, 12 patients had circulating tumor cells and 4 had none. After HIFU treatment, 2 of the 12 patients had converted from presence to absence of circulating cells and the remaining 4 patients remained negative. It is concluded that patients undergoing complete HIFU ablation may demonstrate conversion from presence to absence of circulating tumor-specific marker mRNA, and that HIFU would not enhance the potential risk of metastasis in patients with malignant diseases. (E-mail: mfengwu@yahoo.com ; clinical@haifu.com.cn )

Circulating tumor cells in patients with solid malignancy treated by high-intensity focused ultrasound.

A compilation of reports of biological effects and related ultrasound exposure levels can be useful in the identification of trends in effects data that may be developing in the literature. The exposures in the experiments reviewed were at frequencies used in medicine. For short (10 minutes or less) continuous wave exposure, with the exception of behavioral effects where variable results have been observed, this tabulation did not identify any in vivo or in vitro effects at spatial peak, temporal average (SPTA) intensities less than 100 mW/cm2. However, a number of effects using pulsed sources with SPTA intensities under this level have been reported. There are several frequently recurring topics in recent reports which include developmental effects and microstructure changes at the cellular level. In addition to animal investigations, there are some limited human epidemiological studies reporting an association between medical ultrasound exposure in utero and developmental effects. Although sufficient research has not been completed to draw conclusions, the findings deserve further investigation. A systematic pattern of directed research on a large scale is not apparent. The available data consist of many scattered studies conducted by individual investigators and groups throughout the world.

Compilation of reported biological effects data and ultrasound exposure levels.

Test for the effects of diagnostic levels of ultrasound on the immune response of mice.

Ultrasonically induced hyperthermia (44–45°C for 10 min) and surgical excision were used in the treatment of hamster fibrosarcomas. Both pulsed and continuous wave 3 MHz radiation was used. Rates of metastasis and effectiveness in eliminating the primary tumor were approximately equal with the two methods of treatment.

Ultrasonic treatment of tumors—II: Moderate hyperthermia

Hamster fibrosarcomas were exposed to 1.06 MHz ultrasound at intensities of 90 W/cm 2 in a pulse mode (0.1 sec on, 0.9 sec off) to avoid excessive heating. Tumor temperatures ranged from 19 to 30°C during these exposures. The treatment had no apparent effect on the rate of growth of the primary tumor or on the rate of metastasis.

B. Vives

Papers

Test for the effects of diagnostic levels of ultrasound on the immune response of mice.

Ultrasonic treatment of tumors—II: Moderate hyperthermia

Ultrasonic treatment of tumors-III high intensity, low frequency exposures