ABSTRACT
Gunshot wounds are traumatic events that emergency departments around the country treat on a daily basis. An increasing number of these wounds are being caused by air rifles that shoot ball bearings (ie, BB guns) and, although uncommon, the results can be fatal. The general public and most practitioners may not realize the damage these "toys" can inflict. This article highlights an unfortunate event involving a BB gun accidentally discharged at close range and the consequences. Data from recent and older studies are discussed regarding the firepower of these guns and their potential for injury.
Subject(s)
Brain Injuries/etiology , Firearms , Child , Humans , MaleABSTRACT
Tenascin-C (TN-C) is an extracellular matrix (ECM) protein expressed within remodeling systemic and pulmonary arteries (PAs), where it supports vascular smooth muscle cell (SMC) proliferation. Previously, we showed that A10 SMCs cultivated on native type I collagen possess a spindle-shaped morphology and do not express TN-C, whereas those on denatured collagen possess a well-defined F-actin stress fiber network, a spread morphology, and they do express TN-C. To determine whether changes in cytoskeletal architecture control TN-C, SMCs on denatured collagen were treated with cytochalasin D, which decreased SMC spreading and activation of extracellular signal-regulated kinase 1/2 (ERK1/2), signaling effectors required for TN-C transcription. Next, to determine whether cell shape, dictated by the F-actin cytoskeleton, regulates TN-C, different geometries of SMCs (ranging from spread to round) were engineered on denatured collagen: as SMCs progressively rounded, ERK1/2 activity and TN-C transcription declined. Because RhoA and Rho kinase (ROCK) regulate cell morphology by controlling cytoskeletal architecture, we reasoned that these factors might also regulate TN-C. Indeed, SMCs on denatured collagen possessed higher levels of RhoA activity than those on native collagen, and blocking RhoA or ROCK activities attenuated SMC spreading, ERK1/2 activity, and TN-C expression in SMCs on denatured collagen. Thus, ROCK controls the configuration of the F-actin cytoskeleton and SMC shape in a manner that is permissive for ERK1/2-dependent production of TN-C. Finally, we showed that inhibition of ROCK activity suppresses SMC TN-C expression and disease progression in hypertensive rat PAs. Thus, in addition to its role in regulating vasoconstriction, ROCK also controls matrix production.
Subject(s)
Extracellular Matrix/metabolism , Intracellular Signaling Peptides and Proteins/physiology , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/metabolism , Protein Serine-Threonine Kinases/physiology , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology , Actins/physiology , Animals , Blood Vessels/physiology , Cell Adhesion/physiology , Cell Shape/physiology , Cells, Cultured , Cytoskeleton/physiology , Cytoskeleton/ultrastructure , Disease Progression , Extracellular Signal-Regulated MAP Kinases/metabolism , Hypertension/chemically induced , Hypertension/metabolism , Hypertension/physiopathology , In Vitro Techniques , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Monocrotaline , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/physiology , Myocytes, Smooth Muscle/cytology , Myocytes, Smooth Muscle/physiology , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pulmonary Artery/metabolism , Pulmonary Artery/physiopathology , Rats , Stress, Mechanical , Tenascin/antagonists & inhibitors , Tenascin/biosynthesis , Tenascin/genetics , Tenascin/metabolism , Transcription, Genetic/physiology , Vasoconstriction/physiology , rho-Associated Kinases , rhoA GTP-Binding Protein/physiologyABSTRACT
Tenascin-C (TN-C) expression and matrix metalloproteinase (MMP) activity are induced within remodeling pulmonary arteries (PAs), where they promote cell growth. Because pulmonary vascular disease in children with congenital heart defects is commonly associated with changes in pulmonary hemodynamics, we hypothesized that changes in pulmonary blood flow regulate TN-C and MMPs. To test this, we ligated the left PAs of neonatal pigs. After 12 wk, we evaluated the levels of TN-C and MMPs in control and ligated lung tissue. Modifying pulmonary hemodynamics increased TN-C mRNA and protein expression, MMP activity, and the DNA-binding activity of Egr-1, a transcription factor that has been shown to activate TN-C expression. To link MMP-mediated remodeling of the extracellular matrix to increased TN-C expression and Egr-1 activity, porcine PA smooth muscle cells were cultivated either on denatured type I collagen, which supported TN-C expression and Egr-1 activity, or on native collagen, which had the opposite effect. These data provide a framework for understanding how changes in pulmonary blood flow in the neonate modify the tissue microenvironment and cell behavior.
