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JERUSALEM — Israel attacked Iran’s capital early Friday in strikes that targeted the country’s nuclear program and killed at least two top military officers, raising the potential for an all-out war between the two bitter Middle East adversaries. It appeared to be the most significant attack Iran has faced since its 1980s war with Iraq.

The strikes came amid simmering tensions over Iran’s rapidly advancing nuclear program and appeared certain to trigger a reprisal, with Supreme Leader Ayatollah Ali Khamenei warning that “severe punishment” would be directed at Israel. Israel said Iran had launched drones in an initial response.

Multiple sites around the country were hit, including Iran’s main nuclear enrichment facility, where black smoke could be seen rising into the air.

The leader of Iran’s paramilitary Revolutionary Guard, Gen. Hossein Salami, was confirmed dead, Iranian state television reported, a development that is a significant blow to Tehran’s governing theocracy and an immediate escalation of its long-simmering conflict with Israel.

The chief of staff of Iranian armed forces, Gen. Mohammad Bagheri, was also confirmed dead by Iranian state television. Other top military officials and scientists were believed to have been killed.

In Washington, the Trump administration, which had cautioned Israel against an attack during continued negotiations over Iran’s nuclear enrichment program, said that it had not been involved and warned against any retaliation targeting U.S. interests or personnel.

Still, it seemed likely the U.S. suspected an attack could be in the offing, with Washington on Wednesday pulling some American diplomats from Iraq’s capital and offering voluntary evacuations for the families of U.S. troops in the wider Middle East.

Israeli leaders cast the preemptive assault as a fight for the nation’s survival that was necessary to head off an imminent threat that Iran would build nuclear bombs, though it remains unclear how close the country is to achieving that or whether Iran had actually been planning a strike soon.

“It could be a year. It could be within a few months,” Prime Minister Benjamin Netanyahu said as he vowed to pursue the attack for as long as necessary to “remove this threat.”

“This is a clear and present danger to Israel’s very survival,” he said.

Some 200 Israeli aircraft took part in the opertion, hitting about 100 targets, Israeli army chief spokesman Brig. Gen. Effie Defrin said, adding that the attacks were ongoing.

In the aftermath, Defrin said Iran had launched more than 100 drones toward Israel and that “all the defence systems are acting to intercept the threats.”

Israel, Iraq, Iran and Jordan shut down their airspace to all flights as a precaution.

Khamenei issued a statement carried by the state-run IRNA news agency. It confirmed that top military officials and scientists had been killed in the attack.

Israel “opened its wicked and blood-stained hand to a crime in our beloved country, revealing its malicious nature more than ever by striking residential centers,” Khamenei said.

For Netanyahu, the operation distracts attention from Israel’s ongoing and increasingly unpopular war in Gaza, which is now over 20 months old. There is a broad consensus in the Israeli public that Iran is a major threat, and Israel’s opposition leader, Yair Lapid, a staunch critic of Netanyahu, offered his “full support” for the mission against Iran. But if Iranian reprisals cause heavy Israeli casualties or major disruptions to daily life, Netanyahu could see public opinion quickly shift.

Multiple sites in the Iranian capital were hit in the attack, which Netanyahu said targeted both nuclear and military sites. Also targeted were officials leading Iran’s nuclear program and its ballistic missile arsenal. The International Atomic Energy Agency confirmed that an Israeli strike hit Iran’s uranium enrichment facility at Natanz and said it was closely monitoring radiation levels.

The strike on Iran pushed the Israeli military to its limits, requiring the use of aging air-to-air refuelers to get its fighter jets close enough to attack. It wasn’t immediately clear if Israeli jets entered Iranian airspace or just fired so-called “standoff missiles” over another country. People in Iraq heard fighter jets overhead at the time of the attack. Israel previously attacked Iran from over the border in Iraq.

The potential for an attack had been apparent for weeks as angst built over Iran’s nuclear program.

President Donald Trump on Thursday said that he did not believe an attack was imminent but also acknowledged that it “could very well happen.” Once the attacks were underway, the U.S. Embassy in Jerusalem issued an alert telling American government workers and their families to shelter in place until further notice.

U.S. Secretary of State Marco Rubio said Israel took “unilateral action against Iran” and that Israel advised the U.S. that it believed the strikes were necessary for its self-defense.

“We are not involved in strikes against Iran, and our top priority is protecting American forces in the region,” Rubio said in a statement released by the White House.

Trump is scheduled to attend a meeting of his National Security Council on Friday in the White House Situation Room, where he is expected to discuss the conflict with top advisers. It is not clear if he plans to make public remarks on the strikes.

Israel has long been determined to prevent Iran from developing nuclear weapons, a concern laid bare on Thursday when the Board of Governors at the International Atomic Energy Agency for the first time in 20 years censured Iran over its refusal to work with its inspectors. Iran immediately announced it would establish a third enrichment site in the country and swap out some centrifuges for more-advanced ones.

Even so, there are multiple assessments on how many nuclear weapons it could conceivably build, should it choose to do so. Iran would need months to assemble, test and field any weapon, which it so far has said it has no desire to do. U.S. intelligence agencies also assess Iran does not have a weapons program at this time.

In a sign of the far-reaching implications of the emerging conflict, Israel’s main airport was closed and benchmark Brent crude spiked on news of the attack, rising nearly eight per cent. Both Iran and Israel closed their airspace.

Israeli Defense Minister Israel Katz warned that in the aftermath of the strikes, “missile and drone attacks against Israel and its civilian population are expected immediately.”

“It is essential to listen to instructions from the home front command and authorities to stay in protected areas,” he said in a statement.

As the explosions in Tehran started, Trump was on the lawn of the White House mingling with members of Congress. It was unclear if he had been informed, but the president continued shaking hands and posing for pictures for several minutes.

Trump earlier said he urged Netanyahu to hold off on any action while the administration negotiated with Iran over nuclear enrichment.

“As long as I think there is a (chance for an) agreement, I don’t want them going in because I think it would blow it,” Trump told reporters.

By Jon Gambrell And Josef Federman, The Associated Press

Federman reported from Jerusalem. Associated Press writers Nasser Karimi, Amir Vahdat and Mehdi Fattahi in Tehran, Iran; Melanie Lidman and Sam Mednick Tel Aviv, Israel; Eric Tucker in Washington; and David Rising in Bangkok contributed to this report