As already described by Meakins, MOF may occur following the two "hit" model [14], where the first hit (e.g., liver injury) would trigger an enhanced inflammatory response that might be followed by a "second hit" or insult (e.g., a nosocomial infection) [15].
Experimental data from both human and animal studies suggest that alcohol perturbs the intestinal barrier and its function, which is exacerbated by a "second hit" from traumatic injury.
In childhood cancers such as retinoblastoma, Wilms' tumor and osteosarcoma, changes primarily occur on the paternal allele first, followed by a second hit on the maternal allele [ 5, 6, 22].
For childhood cancers such as retinoblastoma (OMIM #180200), Wilms' tumor (OMIM #194070) and osteosarcoma (OMIM #259500), changes primarily occur on the paternal allele first, followed by a second hit on the maternal allele [ 5, 6].
According to this hypothesis, the disease pathogenesis is sequential, with a first hit consisting in an excessive intrahepatic lipid accumulation, which can be followed by a second hit, resulting in inflammation, hepatocellular damage, and, therefore, NASH.
Altogether, these results indicated that the presence of schwannomas confined to one limb were caused by a first hit, the loss of one copy of 22q12.1q13.33, involving the NF2 gene and affecting at least the schwannoma-initiating cells present in this limb segment, followed by second hits inactivating the remaining functional copy of NF2 as an independent event in each schwannoma developed.
The rationale is discussed in terms of the two-hit somatic mutation theory of Armitage and Doll, with an initial hit produced by the first dose of initiator and expansion of single cells to sizable clones by promotion thereby increasing the probability of a second hit by the second dose of initiator.
The most striking difference is represented by the need of a second hit for triggering thrombosis in naive animals passively infused with human aPLs, while this is not apparently required in models of fetal loss.
The association we observed with MLH1 and PMS2 mutations is consistent with obesity affecting CRC risk by inducing a second hit in the remaining wild-type allele of MLH1 or PMS2.
In a randomized-blinded setting lung injury was induced in 18 pigs by lipopolysaccharide-infusion and a second hit with a short period of ventilator-induced lung stress, followed by a six-hour observation period.
In addition, we demonstrate that inactivation of MLH1 by somatic methylation can constitute a "second hit" in LS-associated tumorigenesis.
