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non relies exclusively on platelets. ADP secreted by platelets, acting via P2Y1 and P2Y12 receptors on the platelet surface, is known to amplify the primary response provided by collagen or thrombin, and to participate in platelet aggregation, thromboxane A2 generation, and thrombus formation under shear stress.39
The release of platelet nucleotides has been found to be critical for in vitro aggregation at lower doses of agonist.9
We have shown that platelets unable to release nucleotides (Munc13-4-deficient) fail to aggregate at a low dose of collagen, and that this defect causes the formation of unstable thrombi (Figure 5), which results in disruption of hemostasis and thrombosis (Figure 6). It has been pro- posed that platelets forming a thrombus can be grouped into two populations: a “core” of contact-dependent high- ly activated platelets and a “shell” of less activated ADP-
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Figure 7. Platelet-specific deletion of Munc13-4 reduces excessive airway constriction to non-specific stimuli (AHR) and lung eosinophilia in a model of asthma. Shown are results from Munc13-4 mutant mice one day after the last airway challenge of an acute allergic airway inflammation model. Naïve: sensitized but not chal- lenged mice. (A) Total respiratory sys- tem resistance (Rrs) at increasing doses of nebulized methacholine (Mch). Circle: mean; error bar: Standard Error of Mean. (B) Rrs at the highest dose of Mch. N: number inside boxes. (C) Representative airway sec- tions stained with PAFS (mucin in red). Scale bar: 20 mm. (D) Mucin volume density at the left lobar bronchus. N=9. (E) Representative lung sections
F (hematoxylin & eosin) and identifica- tion of eosinophils in tissues (insets). Scale bars=20 μm. (F) Eosinophil counts in bronchoalveolar lavage (BAL) fluid. N=9. Color legend in (A) applies to all panels. White line: mean; box: 25th-75th percentile; whiskers: 5th-95th percentile. #P<0.05; †P<0.01; *P<0.001; comparisons are with sen- sitized and challenged Munc13-4+/+
unless otherwise specified.
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