Background: To investigate the effects of different resuscitation fluids on acute lung injury in a rat model of uncontrolled hemorrhagic shock (HS) followed by mimicked infection. Methods; Sixty Sprague-Dawley rats were randomly assigned to one of the five groups (n = 12 per group) to receive the following treatments: (1) control group (group C), surgery, no hemorrhage, and no resuscitation; (2) no fluid resuscitation group; (3) lactated Ringer's solution group; (4) 7.5% hypertonic saline (HTS) group; and (5) hydroxyethyl starch group (group HES). All experimental groups were subjected to three phases: phase I entailed massive hemorrhage with a mean arterial pressure of 35 mm Hg to 40 mm Hg for 60 minutes by tail amputation and followed by mimicked infection by intratracheal administration of lipopolysaccharide 2 mg/kg. The animals in each group were then partially resuscitated with the fluid assigned to die group. Phase II of 60 minutes commenced at tail ligation, involved hemostasis, and return of all the blood initially shed. Phase III was an observation phase with no any further treatment and lasted for 3.5 hours. The survival rate at the end of the phase III was recorded. After Phase III, arterial blood gases were recorded. The wet to dry lung weight ratio, pulmonary microvascular permeability, the expression of transforming growth factor (TGF)-beta 1, and Smad2 were determined. The lung histology was also assessed. Results: HES and HTS solutions were more effective than no fluid resuscitation and lactated Ringer's solution in reducing the detrimental effects of HS and infection on the lungs, as seen by the significantly lower pulmonary microvascular permeability and wet to dry lung weight ratio, the improved arterial blood gases and lower levels of TGF-beta 1 and Smad2 expression in lung tissues. These beneficial effects were most pronounced in the group HES. Conclusions: This study demonstrated that resuscitation with HTS and especially with HES could reduce lung tissue damage and pulmonary edema after severe uncontrolled HS. The TGF-beta 1/Smad2 signaling pathway might play a key role in regulation of pulmonary permeability and formation of pulmonary edema in a rat model of uncontrolled HS and infection.