Causas de Lesão Celular | Tipos | Mecanismos | Reversível e Irreversível | Adaptação | Patologia

Class on the causes, types and mechanisms of cell injuries, reversible and irreversible injuries, adaptation and cell death – Pathology Course – Prof. Dr. Victor Proença – IBAP Courses Class Content • Main causes of cellular injury • Ischemia/Hypoxia • Physical agents: trauma, temperature, radiation, shock • Chemical agents • Infectious agents • Immune reactions • Genetic disorders • Nutritional imbalances • Mechanisms of cellular injury • Cell injury = results from different biochemical mechanisms • Acts on several essential cellular components (mitochondria, cell membranes, protein synthesis and packaging machinery, and DNA) • Mitochondrial damage • Calcium (Ca2+) influx • Plasma membrane damage • Misfolded proteins • DNA damage • ATP depletion • Fundamental cause of cell death by necrosis • Associated with ischemic and chemical (toxic) injury • Reduced oxygen and nutrient supply, mitochondrial damage, and the action of Toxic substances → ATP depletion • Functional and morphological consequences of ATP depletion • Mitochondrial damage • Critical elements in cell injury and death in all its forms → ATP production • Mitochondrial damage due to: increased cytosolic Ca2+, reactive oxygen species, oxygen deprivation. • Mitochondrial gene mutations = cause of some inherited diseases • Role of mitochondria in cell injury and death • Calcium Influx • Important mediators of cell injury • Ischemia and some substances cause = ↑ cytosolic Ca2+ (release from stores + influx) • Increased calcium causes injury by several mechanisms • Oxidative stress (Free Radicals) • Important mechanism of cell damage in many pathological conditions • Free radicals = chemical species that have a single unpaired electron in an outer orbital • Free Radical vs. Antioxidants • Reactive Oxygen Species • Examples of free radicals • Superoxide radical (O2-.) • Hydroperoxyl radical (HO2.) • Hydroxyl radical (OH.) • Hydrogen peroxide (H2O2) • Singlet oxygen (1O2) • Nitrite (HNO2) • Nitric oxide (NO) • Hypochlorite (OCl-) • Peroxynitrite (ONOO-) • Free radical scavenging • Naturally unstable → usually decomposes spontaneously • Enzymatic and non-enzymatic mechanisms for free radical scavenging: vitamins A and E, ascorbic acid, glutathione peroxidase, catalase, superoxide dismutase • Role of reactive oxygen species in cell injury • Defects in membrane permeability • Early loss of selective permeability = a constant feature of most forms of cell injury • Can affect the functions and integrity of all cell membranes • DNA and protein damage • DNA exposure to harmful drugs, radiation, or oxidative stress → very severe DNA damage → cell initiates suicide program (death by apoptosis) • Incorrectly folded proteins also initiate this process