Sublethal injury

There are a number of key features essential for a cell-based model to be effectively predictive of toxicity (Table 14.3). First, as indicated above, it must be sensitive enough to reflect early, sublethal injury and not merely cell death. 

Nony PA and Schnellmann RG. Interactions between collagen IV and collagen-binding integrinsin renal cell repair after sublethal injury. Molecular Pharmacology 60 1226-1234,2001. 

The nature of tubular injury in acute renal failure (ARF) includes reversible sublethal injury (swelling, loss of apical brush border) and lethal injury (necrosis and apoptosis) [1, 2]. Proximal tubular cell death due to ischemic ARF in vivo and hypoxia in vitro results predominantly in necrosis, hence the term acute tubular necrosis or ATM. Apoptotic cell death in ischemic renal injury has been inconsistently demonstrated [3]. When apoptosis has been demonstrated in early ischemic ARF, it is present in the distal tubule [4, 5]. Apoptosis in proximal tubules may play a role in tubular regeneration and was demonstrated to occur at 3 days after ischemic injury in regenerating FT [6]. Thus, the nature of nephrotoxic injury, whether it is tubular dysfunction necrosis or apoptosis is also an important consideration. 

Mackey, B.M. and Derrick, C.M. 1982. The effect of sublethal injury by heating, freezing, drying and gamma-radiation on the duration of the lag phase of Salmonella typhimurium. Journal of Applied Bacteriology 53 243-251. 

Garcia, D., Gomez, N., Condon, S., Raso, J., and Pagan, R. 2003. Pulsed electric field cause sublethal injury in Escherichia coli. Letters in Applied Microbiology 36 140-144. 

Somolinos, M., Garcia, D., Pagan, R., Condon, S., and Manas, P. 2008a. Relationship between sublethal injury and inactivation of yeast cells by the combination of sorbic acid and pulsed electric fields. Applied and Environmental Microbiology 73 3814—3821. 

Wuytack, E.Y., Phuong, D.T., Aertsen, A., Reyns, K.M.F., Marquenie, D., De Ketelaere, B., Masschalk, B., Van Opstal, I., Diels, A.M.J., and Michiels, C.W. 2003. Comparison of sublethal injury induced Salmonella enterica serovar Typhimurium by heat and by different nonthermal treatments. Journal of Food Protection 66 31-37. 

Chemicals with dose related sublethal injury are assumed to show a similar relation of FID to mobility as asphyxiant fire products. For these asphyxiant fire products, the time to incapacitation and its severity usually show a short period of intoxication that is followed by a relatively sharp decline into incapacitation (Purser 2002). The relation between FID or FIC and mobility is shown in Fig. 2 (Purser 2007). For chemicals with concentration related sublethal injury (irritant chemicals) incapacitation occurs when the FIC equals unity, i.e. when the concentration equals the AEGL-2 concentration. The mobility decreases already at lower concentrations (see Fig. 2) due to irritation of nose, throat, lungs and eyes. 

Harm SK, Raval JS, Cramer J, Waters JH, Yazer MH. Haemolysis and sublethal injury of RBCs after routine blood bank marupulations. Transfus Med 2012 22(3) 181-5. 

Wuytack EY, Duong Thi Phuong L, Aertsen A, et al. 2003. Comparison of sublethal injury induced in Salmonella enterica serovar TypMmurium by heat and by different nonthermal treatments. J Food Prot 66 31-37. 

In experimental animals the respiratory system is a primary target of acrolein exposure after inhalation, and there is an inverse relationship between the exposure concentration and the time it takes for death to occur." Inhalation LCso values of 327ppm for 10 minutes and 130ppm for 30 minutes have been reported in rats." Of 57 male rats, 32 died after exposure to 4 ppm for 6 hours/day for up to 62 days. Desquamation of the respiratory epithelium followed by airway occlusion and asphyxiation is the primary mechanism for acrolein-induced mortality in animals." Sublethal acrolein exposure in mice at 3 and 6 ppm suppressed pulmonary antibacterial defense mechanisms. A combination of epithelial cell injury and inhibition of macrophage function may be responsible for acrolein-induced suppression of pulmonary host defense. ... 

Sublethal Measurement as opposed to measurement of cell death is required. Measurement of the noxious substance or a signal transduction event may be too early in the pathogenesis if cell injury as opposed to measurement of adaptive and adverse effects... 

Nishida, K., Miyazawa, Y., Hatano, M., Suzuki, K., Hirose, A., Fukushima, R., Okinaga, K. J. 1998 Reperfusion induces sublethal endothelial injury. Surg Res 79 85-90. 

Figure 3. Proposed mechanism of renal cell repair and regeneration. Healthy renal epithelia are differentiated, quiescent columnar epitheiia. After injury, numerous renal cells die via necrosis and apoptosis depending on the level of insult. However a few cells are sublethally injured and lose cell polarity and many physiological functions. These cells can either initiate the repair process immediately or dedifferentiate into mesenchymal-like cells. Sublethally injured epithelial cells begin to migrate and proliferate to fill in denuded regions of the tubular lumen. The epithelial cells finally redifferentiate back into quiescent tubular cells and regain their polarity and physiological functions.

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