Fig 1.
Of the 13,934-exposed rescue and recovery workers, 92% enrolled in the MMTP. A subset of n = 1720 experienced pulmonary symptoms and had a subspecialty pulmonary evaluation (SPE) before March 2008. Exclusion criteria were applied to form a baseline cohort of N = 801. Those with all biomarkers available were (n = 67) WTC-LI cases; and (n = 118) controls.
Fig 2.
Ager -/- mice are protected from loss of lung function 24 hours after WTC-PM exposure.
24 Hours after a single exposure to WTC-PM, WT mice show significant differences in (A) FEV0.2 (B) compliance and (C) resistance compared to PBS controls. These parameters did not differ between Ager-/- mice exposed to PM and their PBS controls. (D) Airway Hyperreactivity (PC200): WT-PM mice exhibited hyperreactivity, whereas Ager-/—PM did not. A total of WT-PBS = 7, WT-PM = 15, Ager-/—PBS = 8, and Ager -/—PM = 7 mice were analyzed. WT-PBS = 2, WT-PM = 3 and Ager-/—PM = 2 were excluded from FEV0.2 analyses as they did not meet standards outlined in the methods. Additionally, WT-PBS = 1 was excluded from methacholine analysis due to a dosing error.
Fig 3.
PM exposure affects small airways to a greater degree in WT compared to Ager-/- mice.
(A) WT-PM mice had significantly elevated tissue resistance at 1Hz p<0.001 (*). Ager-/—PM had significantly decreased tissue resistance at 1Hz (†) compared the Ager-/—PBS. (B) WT-PM, but not Ager-/—PM mice had significantly (*) higher tissue damping compared to controls. N ≥5 mice per group. WT-PBS = 7, WT-PM = 15, Ager-/—PBS = 8, and Ager-/—PM = 7 mice were analyzed.
Table 1.
Clinical measures, biomarker prevalence and model definition.
Fig 4.
Quantifiable changes to lung histology after PM exposure.
Light microscopic examination of representative hematoxylin and eosin stained sections of lung tissue 24 hours after exposure. (i) Images at 2X while, (ii, iii) are at 40X magnification. (A) WT-PBS exposed mice had normal lung architecture and no infiltrates, whereas (B) WT-PM exposure led to infiltrates, focal acute bronchoalveolar inflammation and interstitial thickening. (C) Ager-/- mice that aspirated PBS and (D) WTC-PM showed no remarkable changes to normal lung architecture. (E) MLI was significantly (*) higher after PM exposure in WT mice but there was no change in Ager-/- mice after PM exposure compared to their controls.
Fig 5.
Cytokines and transcription factors of murine particulate model, biomarker profile in BAL (A-C) and plasma (D-F) expressed as fold change of PM-exposed WT and Ager -/- mice over their respective PBS controls. In BAL, IL-1α (A) and IL-10 (B), had significantly elevated fold change in WT-PM compared to PBS controls (*). Additionally, WT-PM expressed significantly higher fold-change in IL-1α (A) and IL-10 (B) compared to Ager -/—PM. Ager -/—PM expressed significantly higher fold-change in LIF (C) compared to WT-PM (**). LIF expression was also significantly higher in both WT-PM compared to WT-PBS and Ager-/—PM compared to Ager-/—PBS (†). In plasma comparing WT-PM and WT-PBS, IFN-γ (D) and M-CSF (E) were significantly lower, while LPA was higher (F), (*). Additionally, LPA fold-change was lower in Ager-/—PM compared to WT-PM (**). (G) Phosphorylated and Total Levels of Transcription Factors, expressed as MFI relative to β-tubulin. Phosphorylated levels of transcription factors are superimposed in a darker color over the total. Expression of WT is shown in the first two columns of each subdivision, followed by Ager-/- mice. PM exposure is shown with hash marks. Ratio of Phosphorylated/total protein was significant between WT-PM and Ager-/—PM for transcription factors denoted by (*). Ratios significantly different between PM and PBS control are shown by (▼). (H) Western blot of lung homogenates was probed for phosphorylated AKT (pAKT), total AKT (AKT), AGER, and GAPDH as a protein-loading control. Representative images shown; n = 3 for each condition. Relative Phosphorylation of AKT is shown in panel (I) pAKT/total AKT was derived from the primary blots, n = 3 for each condition, mean ± SD. Ager-/- exposed to PM had significantly greater pAKT/AKT compared to PBS controls, (*).