In injured epithelium, fibronectin deposits at the SB to aid in synthesis of a new connective tissue matrix, and to provide substrate for keratinocyte migration to repair wounds. Proximal to the injury, activated keratinocytes, expressing keratin 6, migrate to close the wound and provide resistance to mechanical stress. SB GW786034 keratinocytes also replicate rapidly to refill the wound ; the accelerated differentiation can cause parakeratosis, with nuclei intercalated in the SC. These classical markers of epithelial integrity have not been assessed in the foreskin of sexually active males, but could help determine if foreskin microtrauma is a factor in enhancing STI transmission. Multiple studies have aimed to identify differences among foreskin anatomical sites, to test the hypothesis that the inner foreskin provides a permeable site for pathogen entry. HIV risk has been associated with sub-prepucial wetness, where the inner foreskin is in contact with the penile shaft. However, the epithelial structures associated with foreskin permeability have not been fully explored. Most studies aiming to document the barrier functions of inner foreskin have focused on SC thickness. The SC is composed of consecutive filaments of cross-linked keratin 1, keratin 10, filaggrin, involucrin, cornified envelope proteins, and lipids, conferring strength, elasticity and protection. SC thickness studies have provided contradicting results: one study reported thickening of inner foreskin relative to outer in men with a history of penile infections, two reported no differences, and three documented thinning. In addition to keratinocyte homeostasis and SC integrity, recent evidence indicates that skin permeability is further regulated by the structure of tight junctions in the SG. Involucrin, a terminal marker of keratinocyte maturation, is synthesized in the SS and cross-linked in the SG to provide structural support for TJs. TJ proteins, such as claudins and occludin, form homotypic interactions among adjacent cells and regulate paracellular transport of water, ions, and large molecules. Studies indicate that occludin and claudin 1 form a barrier for extracellular biotin in the healthy human SG, and leakage correlates with their disappearance from the cell membrane. TJ proteins also respond to acute and chronic inflammatory signals that regulate trans-epithelial resistance. Occludin is believed to play its mayor role in the leak transport pathway, which responds to inflammatory stimuli such as IFN-c and TNFa by endocytosis of TJ components and regulates the passage of larger molecules, such as HIV and bacterial products in reconstructed monolayers. The overexpression of occludin has been shown to increase sensitivity of the leak pathway in response to inflammatory cytokines, but its potential role in the entry of pathogens at the pluri-stratified foreskin is unknown. To further examine reasons behind increased STI risk in uncircumcised men, we explored differences among skin factors in the inner and outer foreskin of sexually active men who have sex with men at risk of HIV. We describe differences in the cornified envelope, in TJ proteins in the SG and SS, in secretion of inflammatory cytokines, and in the density of CCR5.