Ionizing radiation induces myofibroblast differentiation via lactate dehydrogenase.

Pulmonary fibrosis is a common and dose-limiting side-effect of ionizing radiation used to treat cancers of the thoracic region. Few effective therapies are available for this disease. Pulmonary fibrosis is characterized by an accumulation of myofibroblasts and excess deposition of extracellular matrix proteins. Although prior studies have reported that ionizing radiation induces fibroblast to myofibroblast differentiation and collagen production, the mechanism remains unclear. Transforming growth factor-ß (TGF-ß) is a key profibrotic cytokine that drives myofibroblast differentiation and extracellular matrix production. However, its activation and precise role in radiation-induced fibrosis are poorly understood. Recently, we reported that lactate activates latent TGF-ß through a pH-dependent mechanism. Here, we wanted to test the hypothesis that ionizing radiation leads to excessive lactate production via expression of the enzyme lactate dehydrogenase-A (LDHA) to promote myofibroblast differentiation. We found that LDHA expression is increased in human and animal lung tissue exposed to ionizing radiation. We demonstrate that ionizing radiation induces LDHA, lactate production, and extracellular acidification in primary human lung fibroblasts in a dose-dependent manner. We also demonstrate that genetic and pharmacologic inhibition of LDHA protects against radiation-induced myofibroblast differentiation. Furthermore, LDHA inhibition protects from radiation-induced activation of TGF-ß. We propose a profibrotic feed forward loop, in which radiation induces LDHA expression and lactate production, which can lead to further activation of TGF-ß to drive the fibrotic process. These studies support the concept of LDHA as an important therapeutic target in radiation-induced pulmonary fibrosis.

An investigation of three physical parameters of PTO entanglements.

The PTO driveline is the most common means of transferring power from a tractor to towed machinery and stationary equipment. While equipment manufacturers install shielding to protect operators and bystanders from coming in contact with operating PTO components (particularly around the knuckle), entanglement is still a cause of some of the most catastrophic agricultural work-related injuries. This study investigated the influence of material type, material length, and angle of material introduction on entanglements with a spinning PTO shaft knuckle. These variables were tested using a laboratory PTO apparatus where 165 entanglements were recorded during the 720 trials conducted. The results indicate that lighter materials, such as cotton thread, have a significantly higher probability of becoming entangled than heavier materials, such as leather bootlaces. Materials that were longer (i.e., extend further below the midline of the PTO knuckle) have higher probabilities of becoming entangled than do shorter materials. The horizontal path that the material traveled across the centerline of the PTO shaft impacted the probability of entanglement. When the angle of intersection of the horizontal path of travel relative to the centerline of the PTO shaft is 90 degrees, or close to 90 degrees, a higher probability of entanglement occurs. All 165 entanglements occurred on the downward rotational side of the PTO knuckle regardless of which side the horizontal path of travel started from. The results of this study provide the first look at understanding the physical phenomena associated with the initial stages of PTO entanglements and set the stage for future research.