transforming-growth-factor-alpha and Stroke

After stroke and other brain injuries, there is a high incidence of respiratory complications such as pneumonia or acute lung injury. The molecular mechanisms that drive the brain-lung interaction post-stroke have not yet been elucidated. We performed transient middle cerebral artery occlusion (MCAO) and sham surgery on C57BL/6J mice and collected bronchoalveolar lavage fluid (BALF), serum, brain, and lung homogenate samples 24 h after surgery. A 92 proteins-panel developed by Olink Proteomics® was used to analyze the content in BALF and lung homogenates. MCAO animals had higher protein concentration levels in BALF than sham-controls, but these levels did not correlate with the infarct volume. No alteration in alveolar-capillary barrier permeability was observed. A total of 12 and 14 proteins were differentially expressed between the groups (FDR < 0.1) in BALF and lung tissue homogenates, respectively. Of those, HGF, TGF-α, and CCL2 were identified as the most relevant to this study. Their protein expression patterns were verified by ELISA. This study confirmed that post-stroke lung damage was not associated with increased lung permeability or cerebral ischemia severity. Furthermore, the dysregulation of HGF, TGF-α, and CCL2 in BALF and lung tissue after ischemia could play an important role in the molecular mechanisms underlying stroke-induced lung damage.

Topics: Animals; Brain Ischemia; Disease Models, Animal; Infarction, Middle Cerebral Artery; Lung; Mice; Mice, Inbred C57BL; Stroke; Transforming Growth Factor alpha

Transforming growth factor-alpha (TGFalpha) is a powerful endogenous mitogen and neurotrophic factor, which has previously been shown to induce a massive proliferative response in the brains of Parkinson's disease model rats injured by an acute neurotoxic lesion. We now show that TGFalpha can also produce a massive proliferative response in rat brains subjected to stroke caused by a middle cerebral artery occlusion (MCAO), even when the growth factor is administered as late as 4 weeks after injury. This combination of stimuli provokes DNA synthesis, shown by 5'-bromo-2-deoxyuridine incorporation, throughout the ependymal layer and subventricular zone (SVZ) of the forebrain during the 4 weeks of growth factor administration. The newly generated cells migrate preferentially along and ventral to the corpus callosum (CC) and external capsule to the site of the injury where many of them differentiate into several site-appropriate neuronal phenotypes in association with near complete (99%) behavioral recovery. We conclude that the injury response of endogenous neural stem cells as well as behavioral recovery can be significantly enhanced by application of TGFalpha, and that this approach represents a potential therapeutic strategy for chronic stroke and other neurological damage in human patients.

Topics: Adult Stem Cells; Analysis of Variance; Animals; Cell Differentiation; Cell Movement; Cell Proliferation; Chronic Disease; Disease Models, Animal; Motor Activity; Neostriatum; Neurogenesis; Neurons; Rats; Recovery of Function; Spatial Behavior; Statistics, Nonparametric; Stroke; Time Factors; Transforming Growth Factor alpha

The cytokine transforming growth factor alpha (TGF alpha) has proangiogenic and proneurogenic effects and can potentially reduce infarct volumes. Therefore, we administered TGF alpha or vehicle directly into the area surrounding the infarct in female mice that received gender-mismatched bone marrow transplants from green fluorescent protein (GFP)-expressing males prior to undergoing permanent middle cerebral artery occlusion. Newborn cells were tracked with bromodeoxyuridine (BrdU) labeling and immunohistochemistry at 90 days after stroke onset. We also studied the ingress of bone marrow-derived cells into the ischemic brain to determine whether such cells contribute to angiogenesis or neurogenesis. Infarct volumes were measured at 90 days poststroke. The results show that TGF alpha led to significant increments in the number of newborn neurons and glia in the ischemic hemisphere. TGF alpha also led to significant increments in the number of bone marrow-derived cells entering into the ischemic hemisphere. Most of these cells did not label with BrdU and represented endothelial cells that incorporated into blood vessels in the infarct border zone. Our results also show that infarct size was significantly reduced in animals treated with TGF alpha compared with controls. These results suggest that TGF alpha can induce angiogenesis, neurogenesis and neuroprotection after stroke. At least part of the pro-angiogenic effect appears to be secondary to the incorporation of bone marrow-derived endothelial cells into blood vessels in the infarct border zone.

Topics: Animals; Bone Marrow Transplantation; Cell Differentiation; Cell Movement; Disease Models, Animal; Endothelial Cells; Female; Graft Survival; Green Fluorescent Proteins; Male; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Nerve Regeneration; Neurogenesis; Neuroglia; Neurons; Recovery of Function; Stroke; Transforming Growth Factor alpha; Treatment Outcome