Sepsis, septic shock, neoplasia, anaplasia, hallmarks of cancer, biology of tumor cells, genetic mechanisms of cancer, proto-oncogenes, tumor suppressor genes, chemical carcinogenesis

23 September Pathophysiology of Sepsis Following an infectious episode, Gram + bacteria release peptidoglycans (exotoxins) and Gram – bacteria release lipopolysaccharides (LPS; endotoxins) Endothelial damage occurs Both produce similar signs and symptoms of sepsis by inducing host cytokines Tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) are expressed by the damaged vascular endothelium Liberation of oxidants by activated neutrophils Inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 and IL-6, are secreted by the monocytes Formation of the fibrin clot “Walling off” infection Formation of thrombi; microvascular occlusion Increased vascular permeability; edema Vascular instability Sepsis Uncontrolled sepsis: “cytokine storm” LPS released from bacteria by LPS-binding protein (LBP). LPS-LBP complex is recognized by the opsonic receptor, CD14. The LPS-LBP-CD14 complex activates Toll- like receptor 4 (TLR4), which in turn signals through the adaptor protein MyD88 and the serine kinase IRAK. This will ultimately lead to the release of cytokines. Endothelium → increased TF and PAI-1 → procoagulant effect → microvascular occlusion Endothelium → oxygen radicals → microvascular occlusion, vascular instability Neutrophils → cytokines → oxygen radicals, lipid mediators → microvascular occlusion, vascular instability Monocytes → lipid mediators → vascular instability Complement → chemotaxis, lysosomal enzymes → vascular instability Microvascular occlusion and vascular instability → coagulopathy, fever, vasodilation, capillary leak → sepsis and multiple organ failure Septic Shock Shock is a hemodynamic disturbance characterized by systemic hypoperfusion resulting in inadequate oxygen supply to vital organs. Shock can be pathogenetically classified as Cardiogenic shock – caused by several mechanisms that reduce the cardiac output Hypovolemic shock – caused by inadequate intravascular volume, as typically seen after massive blood loss due to bleeding Distributive shock – results from massive dilation of blood vessels (increased capacitance of the vascular system) and a subsequent disproportion between the blood volume and the capacitance of the vasculature, as typically seen in septic shock Severe bacterial infection may cause a massive release of bacterial endotoxins, which may stimulate several body reactions. The most important among these is the systemic inflammatory response system, a systemic response mediated by cytokines and mediators of inflammation, which act on arterioles, capillaries, or venules, causing their dilation and creating subsequent pooling of blood in the peripheral circulation Reduced return of blood into the heart decreases the preload with a consequent drop in cardiac output, resulting in hypotension – septic shock Multiple organ failure Multiple organ failure in shock All major organs are involved ARDS, acute respiratory distress syndrome Central nervous system Agitation Apathy Coma Respiratory system Tachypnea Dyspnea ARDS Cardiovascular system Tachycardia Hypotension Hypoxemia Renal system Oliguria Azotemia Liver & gastrointestinal system Ileus Mucosal hemorrhage Abnormal liver function Jaundice Hematopoietic system Disseminated intravascular coagulation Bleeding from vessel puncture sites Neoplasia Classification Clinical, histological Clinical Refers to the overall consequences to the host Clinical behavior can be predicted by pathology Benign Malignant Benign – expansile growth, capsule, homogenous cut surface Malignant – invasive growth, necrosis, lymphatic invasion, nonhomogenous cut surface, hemorrhage, vessel invasion Malignant cells show prominent anaplasia Anaplasia – lack of differentiated features, new features not inherent to tissue of origin Benign cells more closely resemble their tissue type of origin than do malignant cells; well differentiated PAP smears – normal and anaplastic tumor cells from the uterine cervix Note variation in cell size and shape – pleomorphism, with large, hyperchromatic nuclei, abnormal mitotic figures Hallmarks of Cancer Sustaining proliferative signaling Evading growth suppressors Activating invasion and metastasis Enabling replicative immortality Inducing angiogenesis Resisting cell death Biology of Tumor Cells: Biochemistry Most biochemical differences are relative and quantitative rather than qualitative; no biochemical tests for benign vs. malignant cells Unlike normal cells, many malignant cells are “immortal” in v