, 2008) we also observed high CK serum levels in both strains within 3 h of injury. Furthermore, these histomorphometric and sacolermal permeability analysis after 24 h of injury confirms that the delay in muscular regeneration between mouse strains was not due to acute tissue damage induced by B. jararacussu venom. Endogenous danger signals activate Toll-like receptors (TLR 2, 4, and 9) and induce homeostatic or harmful responses, depending on the physiological context, thus explaining contradictory reports showing that TLR4-deficient mice develop harmful noninfectious lung inflammation (Zhao et al., 2010), but not in the model of cardiac ischemia (Zhao et al., 2009) or brain injury (Caso et al., 2007).

In the CDK inhibitor skeletal muscle injury model with cardiotoxin it was suggested that

TLR3 may exert a protective role in muscle regeneration (Mathes and Lafyatis, 2011). MyD88 is utilized by most TLRs with exception of TLR3 that Selleckchem Ipilimumab utilizes TRIF to activate the NF-κB pathway and IRF3 pathway. TLR4 utilizes MyD88 adapter molecule to activate the NF-κB pathway and TRIF adapter molecule to activate the IRF3 pathway inducing production of proinflammatory cytokines (McGettrick and O’Neill, 2010). In the noninfectious lung inflammation, the TLR4 anti-inflammatory signaling is dependent upon a MyD88-independent pathway (Zhao et al., 2010). C3H/HeJ mice used in the present study have a mutation in the cytoplasmic domain caused by substitution of a proline residue for histidine at position 712 in the TLR4 polypeptide chain that halts the activation of both signaling pathways (Poltorak et al., 1998). TLR4-deficient mice showed 10-fold more F4/80-positive macrophages in the injury site in comparison with wild-type mice in 10 DPI, suggesting that such persistence is associated with delayed transition to the early differentiation stage of myogenesis. Delayed muscle repair observed in our study suggests

that TLR4 plays a protective role in muscle regeneration although further studies with knockout mice (MyD88−/− and TRIF−/−) are necessary to determine main signaling pathway involved in the skeletal injury induced by intramuscular injection of B. jararacussu venom. Edema formation and influx of inflammatory cells with subsequent loss of muscle Thymidine kinase mass during later stages of tissue regeneration is regarded as a critical event of venom poisoning caused by snakes of the Bothrops genus (Barbosa et al., 2008; Doin-Silva et al., 2009). The edematogenic effect is related to widespread damage in the local microvasculature due to release of venom proteases (Escalante et al., 2011; Neto and Marques, 2005). Edema formation as evidenced by increased muscle mass was consistently observed in both TLR-deficient and wild-type mice up to 3 days after venom extract injection. Nonetheless, TLR4-deficient mice showed a significant increase in edema formation comparing to TLR4 wild-type mice, which was an indication that TLR4 probably control mechanisms related to edematogenic effect.